The DOI matches its Crossref record; 99 of the 99 references it cites were found in a registry or an index.
Soluble Tumor Necrosis Factor Alpha Promotes Retinal Ganglion Cell Death in Glaucoma via Calcium-Permeable AMPA Receptor Activation
Open accessAbstract
Loss of vision in glaucoma results from the selective death of retinal ganglion cells (RGCs). Tumor necrosis factor α (TNFα) signaling has been linked to RGC damage, however, the mechanism by which TNFα promotes neuronal death remains poorly defined. Using an in vivo rat glaucoma model, we show that TNFα is upregulated by Müller cells and microglia/macrophages soon after induction of ocular hypertension. Administration of XPro1595, a selective inhibitor of soluble TNFα, effectively protects RGC soma and axons. Using cobalt permeability assays, we further demonstrate that endogenous soluble TNFα triggers the upregulation of Ca 2+ -permeable AMPA receptor (CP-AMPAR) expression in RGCs of glaucomatous eyes. CP-AMPAR activation is not caused by defects in GluA2 subunit mRNA editing, but rather reflects selective downregulation of GluA2 in neurons exposed to elevated eye pressure. Intraocular administration of selective CP-AMPAR blockers promotes robust RGC survival supporting a critical role for non-NMDA glutamate receptors in neuronal death. Our study identifies glia-derived soluble TNFα as a major inducer of RGC death through activation of CP-AMPARs, thereby establishing a novel link between neuroinflammation and cell loss in glaucoma. SIGNIFICANCE STATEMENT Tumor necrosis factor α (TNFα) has been implicated in retinal ganglion cell (RGC) death, but how TNFα exerts this effect is poorly understood. We report that ocular hypertension, a major risk factor in glaucoma, upregulates TNFα production by Müller cells and microglia. Inhibition of soluble TNFα using a dominant-negative strategy effectively promotes RGC survival. We find that TNFα stimulates the expression of calcium-permeable AMPA receptors (CP-AMPAR) in RGCs, a response that does not depend on abnormal GluA2 mRNA editing but on selective downregulation of the GluA2 subunit by these neurons. Consistent with this, CP-AMPAR blockers promote robust RGC survival supporting a critical role for non-NMDA glutamate receptors in glaucomatous damage. This study identifies a novel mechanism by which glia-derived soluble TNFα modulates neuronal death in glaucoma.
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“Consistent with the notion that the presence of Ca 2+ -permeable AMPA receptors contributes to the vulnerability of PV-INs, blocking of these receptors attenuates cortical neuron death in an in vitro model of traumatic brain injury; attenuates hippocampal pyramidal neuron loss in a mouse hippocampal slice model of oxygen-glucose deprivation; and attenuates retinal ganglion cells loss in a rat”
From Parvalbumin interneuron vulnerability and brain disorders (2021) · cites this paper as [116]
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Metadata
- Authors
- Cueva Vargas, J. L., Osswald, I. K., Unsain, N., Aurousseau, M. R., Barker, P. A., Bowie, D., & Di Polo, A.
- Affiliations
- McGill University (CA)
- Montreal Neurological Institute and Hospital (CA)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-09-02
- Volume
- 35
- Issue
- 35
- Pages
- 12088-12102
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6605307
- OpenAlex
- W1843574900
- Cited by
- 132
- References
- 99
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 6 · 2023: 7 · 2022: 15 · 2021: 25 · 2020: 18 · 2019: 5 · 2018: 8 · 2017: 11 · 2016: 14
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- McGill University
- Canadian Institutes of Health Research (CIHR-VIH-105439)
- Fonds de Recherche du Québec - Santé
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- glaucoma, retinal ganglion cell death, calcium-permeable AMPA receptors, non-NMDA receptors, Müller cells, microglia, neuroinflammation, ocular hypertension, XPro1595, retinal ganglion cell survival
- MeSH terms
- Animals, Calcium, Carrier Proteins, Choline O-Acetyltransferase, Cobalt, Disease Models, Animal, Glaucoma, Male, Retinal Ganglion Cells, Saline Solution, Hypertonic, Tumor Necrosis Factor-alpha, Up-Regulation, Cell Death, Microglia, Receptors, AMPA, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Rats, Ependymoglial Cells
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