GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis

Nantes, Julia C.; Proulx, Sébastien; Zhong, Jidan; Holmes, Scott A.; Narayanan, Sridar; Brown, Robert A.; Hoge, Richard D.; Koski, Lisa

doi:10.1016/j.neuroimage.2017.01.033

Cited by 38 publications

(53 citation statements)

References 82 publications

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“…Indeed, there is evidence that impaired oligodendrocyte function and/or myelination is accompanied by changes in brain glutamate levels (Gao et al, 2018; Maheras et al, 2018; Nantes et al, 2017; Takanashi et al, 2014; Werner et al, 2001). Moving forward, studies on the role of glutamate in various pathological states should consider the possibility of dual roles for oligodendrocytes as victim and perpetrator of glutamate-related CNS dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

et al. 2019

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SUMMARY Glutamate has been implicated in a wide range of brain pathologies and is thought to be metabolized via the astrocyte-specific enzyme glutamine synthetase (GS). We show here that oligodendrocytes, the myelinating glia of the central nervous system, also express high levels of GS in caudal regions like the midbrain and the spinal cord. Selective removal of oligodendrocyte GS in mice led to reduced brain glutamate and glutamine levels and impaired glutamatergic synaptic transmission without disrupting myelination. Furthermore, animals lacking oligodendrocyte GS displayed deficits in cocaine-induced locomotor sensitization, a behavior that is dependent on glutamatergic signaling in the midbrain. Thus, oligodendrocytes support glutamatergic transmission through the actions of GS and may represent a therapeutic target for pathological conditions related to brain glutamate dysregulation.

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Section: Discussionmentioning

confidence: 99%

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

et al. 2019

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“…Several pioneering MRS studies have revealed significantly lower GABA+ levels in the hippocampus of patients with secondary progressive MS (Cawley et al, ), and lower Glu levels in the sensorimotor and parietal regions in patients with RRMS (Nantes et al, ). This study is the first to show that patients with RRMS exhibit both lower GABA+ and Glu levels in the hippocampus, which may reflect dysfunctional glutamatergic and GABAergic systems.…”

Section: Discussionmentioning

confidence: 99%

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

et al. 2018

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There is growing evidence for dysfunctional glutamatergic excitation and/or gamma-aminobutyric acid (GABA)ergic inhibition in patients with multiple sclerosis (MS). Cognitive impairment may occur during the early stages of MS and hippocampal abnormalities have been suggested as biomarkers. However, researchers have not clearly determined whether changes in hippocampal GABA and glutamate (Glu) levels are associated with cognitive impairment and aberrant neural activity in patients with MS. We used magnetic resonance spectroscopy to measure GABA+ and Glu levels in the left hippocampal region of 29 patients with relapsing-remitting MS and 29 healthy controls (HCs). Resting-state functional connectivity (FC) with the hippocampus was also examined. Compared to HCs, patients exhibited significantly lower GABA+ and Glu levels, which were associated with verbal and visuospatial memory deficits, respectively. Patients also showed decreased FC strengths between the hippocampus and several cortical regions, which are located within the default mode network. Moreover, hippocampal GABA+ levels and Glu/GABA+ ratios correlated with the FC strengths in HCs but not in patients with MS. This study describes a novel method for investigating the complex relationships among excitatory/inhibitory neurotransmitters, brain connectivity and cognition in health and disease. Strategies that modulate Glu and GABA neurotransmission may represent new therapeutic treatments for patients with MS.

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“…BCL-6 5 B cell lymphoma 6 protein; CTNND2 5 catenin delta-2; CSF 5 cerebrospinal fluid; CYP3A4 5 cytochrome P450 3A4; DNMT3B 5 DNA (cytosine-5)-methyltransferase 3B; EAE 5 experimental autoimmune encephalomyelitis; EP300 5 histone acetyltransferase p300; EPHA4 5 ephrin type-A receptor 4; ERBB4 5 receptor tyrosine-protein kinase erbB-4; HGF 5 hepatocyte growth factor; HNF4A 5 hepatocyte nuclear factor 4-alpha; IFN 5 interferon; ITGAM 5 integrin alpha M; LRP1 5 low-density lipoprotein-related protein 1; MET 5 hepatocyte growth factor receptor; NF1 5 neurofibromin; NRP1 5 neuropilin-1; NCOR2 5 nuclear receptor corepressor 2; NF1 5 neurofibromin; OMgp 5 oligodendrocyte-myelin glycoprotein; PBMCs 5 peripheral blood mononuclear cells; In the RP protein data set, there were different proteins correlated with MS or drugs used by MS patients. Three receptors were found in the RP protein data set, which are all major contributors to MS: the first, GABARA1, interacts with GABA to reduce the detrimental effects of glutamate and modulates cytotoxicity of immune cells expressing GABARA [82,90]; the second receptor, IL-12RB2, is involved in IFN-g production by activated T cells and its over-expression has been reported in MS patients [91]; and the third receptor, plexin-A4, negatively regulates T cell-mediated immunity [92]. Three receptors were found in the RP protein data set, which are all major contributors to MS: the first, GABARA1, interacts with GABA to reduce the detrimental effects of glutamate and modulates cytotoxicity of immune cells expressing GABARA [82,90]; the second receptor, IL-12RB2, is involved in IFN-g production by activated T cells and its over-expression has been reported in MS patients [91]; and the third receptor, plexin-A4, negatively regulates T cell-mediated immunity [92].…”

Section: Dnmt3bmentioning

confidence: 99%

“…Hydroxycarboxylic acid receptor 2 (HCAR2) in RP acts as a highaffinity receptor for niacin which, at higher doses, results in enhanced ADIPOQ secretion, decreased lipolysis and apoptosis induction in mature neutrophils [88,89]. Three receptors were found in the RP protein data set, which are all major contributors to MS: the first, GABARA1, interacts with GABA to reduce the detrimental effects of glutamate and modulates cytotoxicity of immune cells expressing GABARA [82,90]; the second receptor, IL-12RB2, is involved in IFN-g production by activated T cells and its over-expression has been reported in MS patients [91]; and the third receptor, plexin-A4, negatively regulates T cell-mediated immunity [92].…”

Section: Dnmt3bmentioning

confidence: 99%

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

Pazhouhandeh

Sahraian

Siadat

et al. 2018

Clinical and Experimental Immunology

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Identification of autoimmune processes and introduction of new autoantigens involved in the pathogenesis of multiple sclerosis (MS) can be helpful in the design of new drugs to prevent unresponsiveness and side effects in patients. To find significant changes, we evaluated the autoantibody repertoires in newly diagnosed relapsing-remitting MS patients (NDP) and those receiving disease-modifying therapy (RP). Through a random peptide phage library, a panel of NDP- and RP-specific peptides was identified, producing two protein data sets visualized using Gephi, based on protein--protein interactions in the STRING database. The top modules of NDP and RP networks were assessed using Enrichr. Based on the findings, a set of proteins, including ATP binding cassette subfamily C member 1 (ABCC1), neurogenic locus notch homologue protein 1 (NOTCH1), hepatocyte growth factor receptor (MET), RAF proto-oncogene serine/threonine-protein kinase (RAF1) and proto-oncogene vav (VAV1) was found in NDP and was involved in over-represented terms correlated with cell-mediated immunity and cancer. In contrast, transcription factor RelB (RELB), histone acetyltransferase p300 (EP300), acetyl-CoA carboxylase 2 (ACACB), adiponectin (ADIPOQ) and phosphoenolpyruvate carboxykinase 2 mitochondrial (PCK2) had major contributions to viral infections and lipid metabolism as significant events in RP. According to these findings, further research is required to demonstrate the pathogenic roles of such proteins and autoantibodies targeting them in MS and to develop therapeutic agents which can ameliorate disease severity.

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GABA and glutamate levels correlate with MTR and clinical disability: Insights from multiple sclerosis

Cited by 38 publications

References 82 publications

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

A systems medicine approach reveals disordered immune system and lipid metabolism in multiple sclerosis patients

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