Glutamate uptake by oligodendrocytes

Pitt, David; Nagelmeier, Iris E.; Wilson, Heather C.; Raine, Cedric S.

doi:10.1212/01.wnl.0000090564.88719.37

Cited by 206 publications

(168 citation statements)

References 31 publications

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“…However, neuronal over-stimulation by glutamate is responsible for both acute (McEwen and Magarinos, 1997;Akins and Atkinson, 2002) and chronic (Coyle and Puttfarcken, 1993;Doble, 1999;Hertz et al, 1999;Obrenovitch et al, 2000;Atlante et al, 2001;Pitt et al, 2003) neurodegenerative conditions. Excitotoxicity results from over-exposure of neurons to high concentrations of glutamate as a result of increased synthesis activity, decreased levels of catabolism, decreased transporter activity, and delayed re-uptake from the synaptic cleft after its release into the synapse.…”

Section: Discussionmentioning

confidence: 99%

Glutamate-related gene expression changes with age in the mouse auditory midbrain

et al. 2007

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Glutamate is the main excitatory neurotransmitter in both the peripheral and central auditory systems. Changes of glutamate and glutamate-related genes with age may be an important factor in the pathogenesis of age-related hearing loss -presbycusis. In this study, changes in glutamate-related mRNA gene expression in the CBA mouse inferior colliculus with age and hearing loss were examined and correlations were sought between these changes and functional hearing measures, such as the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs). Gene expression of 68 glutamate-related genes was investigated using both genechip microarray and real-time PCR (qPCR) molecular techniques for four different age/hearing loss CBA mouse subject groups. Two genes showed consistent differences between groups for both the genechip and qPCR. Pyrroline-5-carboxylate synthetase enzyme (Pycs) showed down-regulation with age and a highaffinity glutamate transporter (Slc1a3) showed up-regulation with age and hearing loss. Since Pycs plays a role in converting glutamate to proline, its deficiency in old age may lead to both glutamate increases and proline deficiencies in the auditory midbrain, playing a role in the subsequent inducement of glutamate toxicity and loss of proline neuroprotective effects. The up-regulation of Slc1a3 gene expression may reflect a cellular compensatory mechanism to protect against age-related glutamate or calcium excitoxicity.

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Section: Discussionmentioning

confidence: 99%

Glutamate-related gene expression changes with age in the mouse auditory midbrain

et al. 2007

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“…25 Expression of EAAT2 in oligodendrocytes is interesting because decreases in EAAT2 immunoreactivity have been observed in the white matter from patients with active multiple sclerosis (MS) lesions, although it is not clear whether this is a primary or secondary effect of MS pathology. 50 Still, blocking glutamate uptake by GLT1 and GLAST in cultured oligodendrocytes or isolated optic nerve leads to cell death, demyelination and axonal damage, suggesting that GLT1 is important for normal oligodendrocyte function. 51 In contrast, although GLT1 mRNA and protein have been detected in neurons in vitro and in vivo, no one has proven that GLT1 functions as a transporter in neurons.…”

Section: Localization Of Glt1mentioning

confidence: 99%

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Lauriat

McInnes

2007

Mol Psychiatry

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The excitatory amino acid transporter 2 (EAAT2) is responsible for the majority of glutamate uptake in the brain and its dysregulation has been associated with multiple psychiatric and neurological disorders. However, investigation of this molecule has been complicated by its complex pattern of alternative splicing, including three coding isoforms and multiple 5 0 -and 3 0 -UTRs that may have a regulatory function. It is likely that these sequences permit modulation of EAAT2 expression with spatial, temporal and or activity-dependent specificity; however, few studies have attempted to delineate the function of these sequences. Additionally, there are problems with the use of antibodies to study protein localization, possibly due to posttranslational modification of critical amino acid residues. This review describes what is currently known about the regulation of EAAT2 mRNA and protein isoforms and concludes with a summary of studies showing dysregulation of EAAT2 in psychiatric and neurological disorders. EAAT2 has been either primarily or secondarily implicated in a multitude of neuropsychiatric diseases in addition to the normal physiology of learning and memory. Thus, this molecule represents an intriguing therapeutic target once we improve our understanding of how it is regulated under normal conditions.

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“…However, the mechanism of oligodendrocyte loss in MS lesions is not well understood. Direct injury by the cytotoxic cytokines TNF-α, IFN-γ and LT-α and reactive oxygen and nitrogen species, apoptotic cell death mediated by Fas/FasL signaling, CD8-mediated cytotoxicity and lysis by γδ-cells (which recognize HSP64 on the oligodendrocyte surface) are among the many factors considered responsible for the observed cell death during the acute phase of the disease [63][64][65][66]. Moreover, deprivation of growth factors may also play a role in the observed oligodendrocyte loss characterized by Tunnelpositive apoptotic oligodendrocytes in chronic MS lesions.…”

Section: Statins Promote Neuroprotection By Inhibiting Demyelination mentioning

confidence: 99%

“…Pathological studies of chronic MS lesions indicate the presence of insufficient numbers of oligodendrocyte progenitor cells and oligodendrocytes for myelin formation [62][63]. The expression of antibodies against oligodendrocytes and their progenitors [64,65], and activation of AMPA/kainite receptors by increased amounts of glutamate [66], are some of the factors that are reported to account for the observed demyelination in inflammatory areas in MS plaques. Reparative therapies with a potential to enhance remyelination, such as statins, provide a promising approach for myelin repair [10,68,69].…”

Section: Statins Support Remyelinationmentioning

confidence: 99%

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

Marković-Pleše

Singh

2008

Future Neurol.

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Statins as inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase are widely used as cholesterol-lowering drugs. Recent studies provide evidence that the anti-inflammatory activity of statins, which is independent of their cholesterol-lowering effects, may have potential therapeutic implications for neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's disease and brain tumors, as well as traumatic spinal cord and brain injuries. Studies with animal models of MS suggest that, in addition to immunomodulatory activities similar to the ones observed with approved MS medications, statin treatment also protects the BBB, protects against neurodegeneration and may also promote neurorepair. Although the initial human studies on statin treatment for MS are encouraging, prospective randomized clinical studies will be required to evaluate their efficacy in the larger patient population. Keywordsblood-brain barrier; immunomodulation; inflammation; multiple sclerosis; neurodegeneration; neuroinflammatory diseases; neurorepair; pleotropic effects; statins Multiple sclerosis (MS) is a chronic CNS disease with a chronic inflammatory response directed against the myelin antigens [1,2]. Immunological studies indicate that autoreactive CD4 + and CD8 + lymphocytes migrate into the CNS following antigen recognition in the peripheral circulation. Once in the CNS, T cells undergo reactivation by abundant myelin antigens and perpetuate an inflammatory response that leads to demyelination and axonal loss †Author for correspondence

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Glutamate uptake by oligodendrocytes

Cited by 206 publications

References 31 publications

Glutamate-related gene expression changes with age in the mouse auditory midbrain

Glutamate-related gene expression changes with age in the mouse auditory midbrain

EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

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