Translating Glutamate: From Pathophysiology to Treatment

Translational Schizophrenia Research Center, Nathan Kline Institute/Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Science translational medicine (Impact Factor: 15.84). 09/2011; 3(102):102mr2. DOI: 10.1126/scitranslmed.3002804
Source: PubMed


The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autism, and depression-that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration-approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine-sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.

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Available from: Chi Ming Lee
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    • "Glutamate is the most abundant amino acid neurotransmitter in the mammalian brain. Glutamatergic neurotransmission has drawn attention for its role in the pathophysiology of schizophrenia (Javitt et al., 2011; Krystal, 2008; Yang et al., 2013; Zink and Correll, 2015). There are two types of glutamate receptors: metabotropic and ionotropic receptors. "
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    ABSTRACT: Background: The cystine/glutamate antiporter system xc(-), playing a critical role in the regulation of glutamate release, might be implicated in the pathogenesis of schizophrenia. This study examined whether peripheral expressions of the system xc(-) subunits are characteristic of schizophrenia. Methods: Expression of system xc(-) genes including SLC3A2 and SLC7A11 in peripheral WBCs of patients with schizophrenia and healthy individuals were measured using quantitative PCR. Both psychotropic-free and medicated patients with schizophrenia were recruited. Results: A total of 96 schizophrenia patients (48 medicated and 48 drug-free) and 96 healthy individuals were enrolled. The mRNA expression levels using the 2(-ΔΔC)T Method of both SLC3A2 and SLC7A11 in WBCs of schizophrenia patients were markedly lower than that of healthy individuals (0.22 and 0.48, respectively, the mRNA expression level of normal controls was normalized to 1). There was no significant difference between medicated and drug-free patients in the mRNA expressions of both SLC3A2 and SLC7A11. The Receiver Operating Characteristics (ROC) analysis of SLC3A2 mRNA levels using ΔΔCT values for drug-free schizophrenia patients vs. healthy controls determined an optimal cutoff value, 0.801, with high sensitivity (1.000) and modest specificity (0.694) (area under curve of ROC = 0.794). Conclusion: This is the first study indicating that the peripheral mRNA expression levels of SLC7A11 and SLC3A2 may be lower in patients with schizophrenia than healthy individuals. The finding supports the hypo-glutamatergic neurotransmission hypothesis in schizophrenia. Whether mRNA expression of system xc(-) subunits genes, particularly SLC3A2, could serve as a potential biomarker of schizophrenia needs further studies.
    Full-text · Article · Oct 2015 · Journal of Psychiatric Research
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    • "Excessive glutamatergic signaling at mGluR5 synapses is a well-characterized FXS phenotype (Bear et al., 2004). Moreover, it is known that mGluR5 can be rapidly down-regulated in response to overstimulation (Javitt et al., 2011). Our finding of reduced levels of mGluR5 in the synaptosome-enriched fraction in Fmr1 KO mice is in accord with this idea and is in agreement with a previous study (Giuffrida et al., 2005). "
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    ABSTRACT: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and single genomic cause of autism spectrum disorders. It is caused by the absence of fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 KO), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates. To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-(14)C]leucine method in vehicle- and R-baclofen-treated WT and Fmr1 KO mice. We further probed signaling pathways involved in regulation of protein synthesis. Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mTOR pathway particularly in synaptosome-enriched fractions, but it had no effect on ERK1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in mGluR5 expression in frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug. Our results suggest that treatment via activation of the GABAB system warrants further study in patients with FXS. Published by Oxford University Press on behalf of CINP 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    Full-text · Article · Mar 2015 · The International Journal of Neuropsychopharmacology
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    • "Research investigating the clinical effectiveness of glutamate agonists for SCZ, Parkinson's, and obsessive–compulsive disorder (Javitt, 2012) suggests new avenues of pharmacotherapy for negative symptoms in addition to the D2 receptor antagonists currently used to manage psychotic symptoms. Alternatively , the clinical effectiveness of glutamate antagonists, such as ketamine for autism and treatment-resistant depression, has suggested a dynamic role for glutamate in brain across a wide array of psychiatric disorders (Javitt et al., 2011). Importantly, glutamate has been most recently implicated in schizophrenia in the largest genome-wide association study of schizophrenia to date (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). "
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    ABSTRACT: Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N=507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Mar 2015 · Schizophrenia Research
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