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Tarang Khare,
Shraddha Pai,
Karolis Koncevicius,
Mrinal Pal,
Edita Kriukiene,
Zita Liutkeviciute,
Manuel Irimia,
Peixin Jia,
Carolyn Ptak,
Menghang Xia, [......],
Anaies Nazarians,
Denise Belsham,
Albert H C Wong,
Benjamin J Blencowe,
Sun Chong Wang,
Philipp Kapranov,
Rafal Kustra, Viviane Labrie,
Saulius Klimasauskas,
Arturas Petronis
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ABSTRACT: The 5-methylcytosine (5-mC) derivative 5-hydroxymethylcytosine (5-hmC) is abundant in the brain for unknown reasons. Here we characterize the genomic distribution of 5-hmC and 5-mC in human and mouse tissues. We assayed 5-hmC by using glucosylation coupled with restriction-enzyme digestion and microarray analysis. We detected 5-hmC enrichment in genes with synapse-related functions in both human and mouse brain. We also identified substantial tissue-specific differential distributions of these DNA modifications at the exon-intron boundary in human and mouse. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural contexts. This pattern was replicated in multiple independent data sets and with single-molecule sequencing. Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain.
Nature Structural & Molecular Biology 09/2012; 19(10):1037-43. · 12.71 Impact Factor
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ABSTRACT: Understanding the origins of normal and pathological behavior is one of the most exciting opportunities in contemporary biomedical research. There is increasing evidence that, in addition to DNA sequence and the environment, epigenetic modifications of DNA and histone proteins may contribute to complex phenotypes. Inherited and/or acquired epigenetic factors are partially stable and have regulatory roles in numerous genomic activities, thus making epigenetics a promising research path in etiological studies of psychiatric disease. In this article, we review recent epigenetic studies examining the brain and other tissues, including those from individuals with schizophrenia (SCZ) and bipolar disorder (BPD). We also highlight heuristic aspects of the epigenetic theory of psychiatric disease and discuss the future directions of psychiatric epigenetics.
Trends in Genetics 05/2012; 28(9):427-35. · 10.06 Impact Factor
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ABSTRACT: D-serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of D-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of D-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by D-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades D-serine as well. D-serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice--the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of D-serine to ALS mice dramatically lowers cord levels of D-serine, leading to changes in the onset and survival very similar to SR deletion. D-serine treatment also increases cord levels of the alanine-serine-cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases D-serine is not known, these results strongly suggest that SR and D-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
Journal of Neurochemistry 11/2011; 120(4):598-610. · 4.06 Impact Factor
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ABSTRACT: The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients.
Neuropharmacology 02/2011; 62(3):1484-503. · 4.81 Impact Factor
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Masoud Vedadi,
Dalia Barsyte-Lovejoy,
Feng Liu,
Sylvie Rival-Gervier,
Abdellah Allali-Hassani, Viviane Labrie,
Tim J Wigle,
Peter A Dimaggio,
Gregory A Wasney,
Alena Siarheyeva, [......],
Aled Edwards,
Bryan L Roth,
William P Janzen,
Benjamin A Garcia,
Arturas Petronis,
James Ellis,
Peter J Brown,
Stephen V Frye,
Cheryl H Arrowsmith,
Jian Jin
Nature Chemical Biology 01/2011; 7(9):648. · 14.69 Impact Factor
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Masoud Vedadi,
Dalia Barsyte-Lovejoy,
Feng Liu,
Sylvie Rival-Gervier,
Abdellah Allali-Hassani, Viviane Labrie,
Tim J Wigle,
Peter A Dimaggio,
Gregory A Wasney,
Alena Siarheyeva, [......],
Aled Edwards,
Bryan L Roth,
William P Janzen,
Benjamin A Garcia,
Arturas Petronis,
James Ellis,
Peter J Brown,
Stephen V Frye,
Cheryl H Arrowsmith,
Jian Jin
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ABSTRACT: Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
Nature Chemical Biology 01/2011; 7(8):566-74. · 14.69 Impact Factor
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ABSTRACT: L-Serine-O-phosphate (L-SOP), the precursor of l-serine, is an agonist at group III metabotropic glutamate receptors. Despite the interest in L-SOP, very few articles have reported its brain levels. Here we report a convenient and reproducible method for simultaneous analysis of L-SOP and several other important amino acids in brain tissue using high-performance liquid chromatography (HPLC) with fluorimetric detection after derivatization with o-phthaldialdehyde and N-isobutyl-L-cysteine. Analyses were carried out in rat whole brain and cerebellum and in mouse whole brain, forebrain, amygdala, and prefrontal cortex. The method should be useful for future comprehensive neurochemical and pharmacological studies on neuropsychiatric disorders.
Analytical Biochemistry 10/2010; 405(2):260-2. · 3.00 Impact Factor
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Biological Psychiatry 04/2010; 120(1-3):236-7. · 8.28 Impact Factor
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Viviane Labrie,
Ryutaro Fukumura,
Anjali Rastogi,
Laura J Fick,
Wei Wang,
Paul C Boutros,
James L Kennedy,
Mawahib O Semeralul,
Frankie H Lee,
Glen B Baker,
Denise D Belsham,
Steven W Barger,
Yoichi Gondo,
Albert H C Wong,
John C Roder
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ABSTRACT: Abnormal N-methyl-d-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. d-serine is an important NMDAR modulator, and to elucidate the role of the d-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and dramatically reduced d-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were exacerbated by an NMDAR antagonist and ameliorated by d-serine or the atypical antipsychotic clozapine. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Transcript levels altered by the Srr mutation were also normalized by d-serine or clozapine treatment. Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis.
Human Molecular Genetics 06/2009; 18(17):3227-43. · 7.64 Impact Factor
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ABSTRACT: Activation of the N-methyl-D-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO), were examined in behavioral tests of learning and memory. In the Morris water maze task (MWM), mice carrying the hypofunctional Dao1(G181R) mutation demonstrated normal acquisition of a single platform location but had substantially improved memory for a new target location in the subsequent reversal phase. Furthermore, Dao1(G181R) mutant animals exhibited an increased rate of extinction in the MWM that was similarly observed following pharmacological administration of D-serine (600 mg/kg) in wild-type C57BL/6J mice. In contextual and cued fear conditioning, no alterations were found in initial associative memory recall; however, extinction of the contextual fear memory was facilitated in mutant animals. Thus, an augmented level of D-serine resulting from reduced DAO activity promotes adaptive learning in response to changing conditions. The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes.
Learning & memory (Cold Spring Harbor, N.Y.) 02/2009; 16(1):28-37. · 4.08 Impact Factor
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ABSTRACT: Several compounds that promote activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site have been proposed as treatments for schizophrenia, but the impact of these putative antipsychotics on anxiety remains unclear. In this study, we employed genetic and pharmacological mouse models of altered NMDAR glycine site function to examine the effects of these proposed treatments in unconditioned tests of anxiety. In the elevated plus-maze, open field, and novel object test, homozygous Grin1(D481N) mutant mice that have a five-fold reduction in NMDAR glycine affinity demonstrated an anxiolytic-like phenotype. In contrast, d-serine, a direct activator of the NMDAR glycine site, and ALX-5407, a glycine transporter-1 (GlyT-1) inhibitor, enhanced anxiety-like behaviors in wild-type and Grin1(D481N) mutant animals. Homozygous Dao1(G181R) mutant mice that lack function of the d-serine catabolic enzyme, d-amino acid oxidase (DAO), displayed an elevation in anxiety. Deficient DAO activity also reversed the anxiolytic effects of diminished NMDAR function in mice carrying both the homozygous Grin1(D481N) and Dao1(G181R) mutation. Thus, a direct agonist of the NMDAR glycine site, a GlyT-1 inhibitor, and suppression of DAO function induced anxiogenic-like behaviors. Consequently, application of these treatments for amelioration of schizophrenic symptoms necessitates caution as an enhancement of comorbid anxiety disorders may result.
Pharmacology Biochemistry and Behavior 11/2008; 91(4):610-20. · 2.53 Impact Factor
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ABSTRACT: Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia.
We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice.
Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity.
Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty.
Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.
Psychopharmacologia 08/2008; 200(2):217-30. · 4.08 Impact Factor
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ABSTRACT: The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.
Neuropsychopharmacology 05/2008; 33(5):1004-18. · 7.99 Impact Factor
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ABSTRACT: Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.
This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, D-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801.
C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings.
Clozapine (3 mg/kg) and D-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by D-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, D-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801.
D-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.
Psychopharmacologia 05/2005; 179(1):54-67. · 4.08 Impact Factor
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ABSTRACT: Hypofunction of the N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a d-serine/glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. This review outlines the complex regulation of endogenous NMDAR d-serine/glycine site agonists and explores their contribution to schizophrenia pathogenesis and their potential clinical utility. Genetic studies have associated genes influencing NMDAR d-serine/glycine site activation with an increased susceptibility to schizophrenia. Postmortem studies have identified abnormalities in several transcripts affecting d-serine/glycine site activity, consistent with in vivo reports of alterations in levels of endogenous d-serine/glycine site agonists and antagonists. Genetically modified mice with aberrant NMDAR d-serine/glycine site function model certain features of the negative and cognitive symptoms of schizophrenia, and similar behavioral abnormalities have been observed in other candidate genes models. Compounds that directly activate the NMDAR d-serine/glycine site or inhibit glycine transport have demonstrated beneficial effects in preclinical models and clinical trials. Future pharmacological approaches for schizophrenia treatment may involve targeting enzymes that affect d-serine synthesis and metabolism.
Neuroscience & Biobehavioral Reviews.
