AMPA receptors are the major mediators of excitotoxic death in mature oligodendrocytes

Leuchtmann, Elizabeth A; Ratner, Andrea E; Vijitruth, Rattanavijit; Qu, Yun; McDonald, John W.

doi:10.1016/j.nbd.2003.07.004

Cited by 24 publications

(19 citation statements)

References 40 publications

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“…These observations were validated at both mRNA and protein levels for AMPAGluR1. Such up-regulation of AMPA-GluR may render lupus brains susceptible to GluR-mediated excitotoxicity (59).…”

Section: Discussionmentioning

confidence: 99%

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

Alexander¹,

Jacob²,

Bao³

et al. 2005

The Journal of Immunology

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The role of complement activation in the brains of MRL/lpr lupus mice was determined using the potent C3 convertase inhibitor, CR1-related y (Crry), administered both as an overexpressing Crry transgene and as Crry-Ig. Prominent deposition of complement proteins C3 and C9 in brains of MRL/lpr mice was indicative of complement activation and was significantly reduced by Crry. Apoptosis was determined in brain using different independent measures of apoptosis, including TUNEL staining, DNA laddering, and caspase-3 activity, all of which were markedly increased in lupus mice and could be blocked by inhibiting complement with Crry. Complement activation releases inflammatory mediators that can induce apoptosis. The mRNA for potentially proinflammatory proteins such as TNFR1, inducible NO synthase, and ICAM-1 were up-regulated in brains of lupus mice. Crry prevented the increased expression of these inflammatory molecules, indicating that the changes were complement dependent. Furthermore, microarray analysis revealed complement-dependent up-regulation of glutamate receptor (AMPA-GluR) expression in lupus brains, which was also validated for AMPA-GluR1 mRNA and protein. Our results clearly demonstrate that apoptosis is a prominent feature in lupus brains. Complement activation products either directly and/or indirectly through TNFR1, ICAM-1, inducible NO synthase, and AMPA-GluR, all of which were altered in MRL/lpr mouse brains, have the potential to induce such apoptosis. These findings present the exciting possibility that complement inhibition is a therapeutic option for lupus cerebritis.

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“…These observations were validated at both mRNA and protein levels for AMPAGluR1. Such up-regulation of AMPA-GluR may render lupus brains susceptible to GluR-mediated excitotoxicity (59).…”

Section: Discussionmentioning

confidence: 99%

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

Alexander¹,

Jacob²,

Bao³

et al. 2005

The Journal of Immunology

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“…All animal procedures were approved by the University of Colorado Institutional Animal Care and Use Committee or the Institutional Animal Care and Use Committee of the Cleveland Clinic Foundation. Mouse lines used were PLP null mice (Pende et al, 1994;Klugmann et al, 1997;Yuan et al, 1998;Deng et al, 2003Deng et al, , 2004Káradó ttir et al, 2005;Salter and Fern, 2005;Narayanan et al, 2009), GluR2null mice (Iihara et al, 2001;Narayanan et al, 2009;Tyler et al, 2009;Wahl et al, 2014), and ␣v integrin heterozygous mice (Bader et al, 1998;Fyffe-Maricich et al, 2011Ishii et al, 2012). All lines were crossed with PLP-EGFP mice (Barres et al, 1994;Ahlgren et al, 1997;Mallon et al, 2002;Huang et al, 2011), in which the Plp1 promoter drives EGFP in cells of the oligodendroglial lineage.…”

Section: Methodsmentioning

confidence: 99%

“…PLP and its smaller isoform DM20 are also expressed in OPCs. AMPA treatment of OPCs in culture causes an increased association of ␣v integrin with PLP and the GluR2 subunit of the AMPA glutamate receptor, decreasedbindingtofibronectin,andincreasedOPCmigration (Bradbury et al, 2002;Gudz et al, 2006;Karimi-Abdolrezaee et al, 2012;Starkey et al,2012).Toinvestigatethephysiologicalimpactofthiscomplexinvivo, we examined the expression of PLP, ␣v integrin, AMPA GluR subunits, and fibronectin in the cerebellum of PLP-EGFP mice at P4 (Fig. 1).…”

Section: Plp ␣V Integrin Glur2 and Fibronectin Expression In Vivomentioning

confidence: 99%

“…Glutamate signaling influences many aspects of neural progenitor development, including survival, proliferation, migration, and differentiation (for review, see Jansson and Akerman, 2014). Oligodendrocyte lineage cells express metabotropic and ionotropic AMPA, NMDA, and kainate glutamate receptors and are exposed to glutamate in both the gray and the white matter during development as well as to high levels of glutamate after injury or disease (Pende et al, 1994;Yuan et al, 1998;Deng et al, 2003Deng et al, , 2004Káradó ttir et al, 2005;Salter and Fern, 2005). Since glutamate receptor stimulation alters proliferation, migration, vesicle release, and differentiation of cultured oligodendrocyte cells (Pende et al, 1994;Holtzclaw et al, 1995;Gallo et al, 1996;Behar et al, 1999;Haydar et al, 2000;Stidworthy et al, 2004;Gudz et al, 2006;Platel et al, 2007;Bagayogo and Dreyfus, 2009;Zhang et al, 2009;Frühbeis et al, 2013;Hossain et al, 2014), it is important to understand how neurotransmitters impact oligodendrocyte precursor cells (OPCs) in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Myelin Proteolipid Protein Complexes with v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

Harlow

Saul²,

Komuro

et al. 2015

Journal of Neuroscience

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In previous studies, stimulation of ionotropic AMPA/kainate glutamate receptors on cultured oligodendrocyte cells induced the formation of a signaling complex that includes the AMPA receptor, integrins, calcium-binding proteins, and, surprisingly, the myelin proteolipid protein (PLP). AMPA stimulation of cultured oligodendrocyte progenitor cells (OPCs) also caused an increase in OPC migration. The current studies focused primarily on the formation of the PLP-␣v integrin-AMPA receptor complex in vivo and whether complex formation impacts OPC migration in the brain. We found that in wild-type cerebellum, PLP associates with ␣v integrin and the calciumimpermeable GluR2 subunit of the AMPA receptor, but in mice lacking PLP, ␣v integrin did not associate with GluR2. Live imaging studies of OPC migration in ex vivo cerebellar slices demonstrated altered OPC migratory responses to neurotransmitter stimulation in the absence of PLP and GluR2 or when ␣v integrin levels were reduced. Chemotaxis assays of purified OPCs revealed that AMPA stimulation was neither attractive nor repulsive but clearly increased the migration rate of wild-type but not PLP null OPCs. AMPA receptor stimulation of wild-type OPCs caused decreased cell-surface expression of the GluR2 AMPA receptor subunit and increased intracellular Ca 2ϩ signaling, whereas PLP null OPCs did not reduce GluR2 at the cell surface or increase Ca 2ϩ signaling in response to AMPA treatment. Together, these studies demonstrate that PLP is critical for OPC responses to glutamate signaling and has important implications for OPC responses when levels of glutamate are high in the extracellular space, such as following demyelination.

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“…This, of course, sets the stage for oxidative stress and cell death within these unique glial elements. The glutamate-mediated excitotoxic death of oligodendrocytes occurs predominantly by necrosis, releasing large amounts of iron, and contributes to pathogenesis in demyelinating disease (82,83). There is growing appreciation of the process of demyelination of brain white matter in the development and progression of AD.…”

Section: Cholesterolmentioning

confidence: 99%

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

Lane

Farlow

2005

Journal of Lipid Research

157

128

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AMPA receptors are the major mediators of excitotoxic death in mature oligodendrocytes

Cited by 24 publications

References 40 publications

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

Myelin Proteolipid Protein Complexes with v Integrin and AMPA Receptors In Vivo and Regulates AMPA-Dependent Oligodendrocyte Progenitor Cell Migration through the Modulation of Cell-Surface GluR2 Expression

Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease

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