Glutamatergic Modulators: The Future of Treating Mood Disorders?

Zarate, Carlos A.; Machado‐Vieira, Rodrigo; Henter, Ioline D.; Ibrahim, Lobna; Diazgranados, Nancy; Salvadore, Giacomo

doi:10.3109/10673229.2010.511059

Cited by 209 publications

(102 citation statements)

References 122 publications

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“…Similar to memantine, no study has taken into consideration the inflammatory status of the sample population. Several proprietary drugs with effects on NMDA systems are under varying stages of development and evaluation, and the reader is referred to other more in depth articles focusing on this topic (Niciu et al, 2014a;Sanacora et al, 2012;Zarate et al, 2010).…”

Section: Preclinical and Clinical Studies: Translational Relevancementioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

383

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Preclinical and Clinical Studies: Translational Relevancementioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

383

299

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“…Several lines of evidence suggest that dysfunction of the glutamate neurotransmitter system is also associated with the pathophysiology of mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BP) (Hashimoto, 2009(Hashimoto, , 2011Sanacora, Zarate, Krystal, & Manji, 2008;Tokita, Yamaji, & Hashimoto, 2012;Zarate et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Short‐ and long‐term antidepressant effects of ketamine in a rat chronic unpredictable stress model

et al. 2017

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“…Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. [1][2][3][4][5][6] The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors.…”

Section: Introductionmentioning

confidence: 99%

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

Lyddon

Navarrett²,

Dracheva³

2012

jpn

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IntroductionGlutamate is the main neurotransmitter responsible for excitatory neurotransmission throughout the brain. Glutamate serves as a ligand for G-protein coupled metabotropic and ionotropic (iGluRs) receptors. The latter consists of N-methyl-D-aspartate, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate (KA) subtypes. Glutamate dysfunction has been linked to numerous diseases, including schizophrenia, bipolar disorder and major depressive disorder. 1-6The AMPA and KA receptors are ligand-gated nonselective cation channels that mediate fast excitatory neurotransmission. Each receptor is a tetramer composed of a combination of subunits encoded by separate genes, GluA1-4 for AMPA, and GluK1-3 and KA1-2 for KA receptors. Individual subunit transcripts undergo posttranscriptional modifications that substantially alter the structure and function of the resulting receptors. Alternative splicing of GluA1-4 generates 2 different variants of each subunit (flip or flop), forming AMPA receptors with distinct kinetic properties. [7][8][9] In addition, AMPA and KA receptor transcripts can be modified by RNA editing. 10The most frequent RNA editing process in eukaryotes involves conversion of adenosine to inosine catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes.11 As inosine is interpreted as a guanosine during splicing and translation, the editing event can result in recoding. A total of Background: Dysfunction of glutamate neurotransmission has been implicated in the pathology of schizophrenia and bipolar disorder, and one mechanism by which glutamate signalling can be altered is through RNA editing of ionotropic glutamate receptors (iGluRs). The objectives of the present study were to evaluate the editing status of iGluRs in the human prefrontal cortex, determine whether iGluR editing is associated with psychiatric disease or suicide and evaluate a potential association between editing and alternative splicing in the α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) iGluR subunits' pre-mRNA. Methods: We studied specimens derived from patients with antemortem diagnoses of bipolar disorder (n = 31) or schizophrenia (n = 34) who died by suicide or other causes, and from psychiatrically healthy controls (n = 34) who died from causes other than suicide. The RNA editing at all 8 editing sites within AMPA (GluA2-4 subunits) and kainate (GluK1-2 subunits) iGluRs was analyzed using a novel real-time quantitative polymerase chain reaction assay. Results: No differences in editing were detected among schizophrenia, bipolar or control groups or between suicide completers and patients who died from causes other than suicide. The editing efficiency was significantly higher in the flop than in the flip splicoforms of GluA3-4 AMPA subunits (all p < 0.001). Limitations: The study is limited by the near absence of specimens from medicationnaive psychiatric patients and considerable variation in medication regimens among individuals, both of which introduce considerable uncertainty into the ana...

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Glutamatergic Modulators: The Future of Treating Mood Disorders?

Cited by 209 publications

References 122 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Short‐ and long‐term antidepressant effects of ketamine in a rat chronic unpredictable stress model

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

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