Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity
Anti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and ce...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/1/248 |
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| author | Mercedeh Farhat Sabet Sumanta Barman Mathias Beller Sven G. Meuth Nico Melzer Orhan Aktas Norbert Goebels Tim Prozorovski |
| author_facet | Mercedeh Farhat Sabet Sumanta Barman Mathias Beller Sven G. Meuth Nico Melzer Orhan Aktas Norbert Goebels Tim Prozorovski |
| author_sort | Mercedeh Farhat Sabet |
| collection | DOAJ |
| description | Anti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and cerebrospinal fluid findings. Indeed, autoantibodies (AABs) against the GluN1 (NR1) subunit of the NMDAR diminish glutamatergic transmission in both neurons and oligodendrocytes, leading to a state of NMDAR hypofunction. Considering the vital role of oligodendroglial NMDAR signaling in neuron-glia communication and, in particular, in tightly regulated trophic support to neurons, the influence of GluN1 targeting on the physiology of myelinated axon may be of importance. We applied a myelinating spinal cord cell culture model that contains all major CNS cell types, to evaluate the effects of a patient-derived GluN1-specific monoclonal antibody (SSM5) on neuronal and myelin integrity. A non-brain reactive (12D7) antibody was used as the corresponding isotype control. We show that in cultures at the late stage of myelination, prolonged treatment with SSM5, but not 12D7, leads to neuronal damage. This is characterized by neurite blebbing and fragmentation, and a reduction in the number of myelinated axons. However, this significant toxic effect of SSM5 was not observed in earlier cultures at the beginning of myelination. Anti-GluN1 AABs induce neurodegenerative changes and associated myelin loss in myelinated spinal cord cultures. These findings may point to the higher vulnerability of myelinated neurons towards interference in glutamatergic communication, and may refer to the disturbance of the NMDAR-mediated oligodendrocyte metabolic supply. Our work contributes to the understanding of the emerging association of NMDAR encephalitis with demyelinating disorders. |
| first_indexed | 2024-03-09T03:31:27Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T03:31:27Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-631f450135574793972c7e241b1d512b2023-12-03T14:54:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124124810.3390/ijms24010248Myelinating Co-Culture as a Model to Study Anti-NMDAR NeurotoxicityMercedeh Farhat Sabet0Sumanta Barman1Mathias Beller2Sven G. Meuth3Nico Melzer4Orhan Aktas5Norbert Goebels6Tim Prozorovski7Department of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyInstitut für Mathematische Modellierung Biologischer Systeme, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyDepartment of Neurology, Medical Faculty, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, GermanyAnti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and cerebrospinal fluid findings. Indeed, autoantibodies (AABs) against the GluN1 (NR1) subunit of the NMDAR diminish glutamatergic transmission in both neurons and oligodendrocytes, leading to a state of NMDAR hypofunction. Considering the vital role of oligodendroglial NMDAR signaling in neuron-glia communication and, in particular, in tightly regulated trophic support to neurons, the influence of GluN1 targeting on the physiology of myelinated axon may be of importance. We applied a myelinating spinal cord cell culture model that contains all major CNS cell types, to evaluate the effects of a patient-derived GluN1-specific monoclonal antibody (SSM5) on neuronal and myelin integrity. A non-brain reactive (12D7) antibody was used as the corresponding isotype control. We show that in cultures at the late stage of myelination, prolonged treatment with SSM5, but not 12D7, leads to neuronal damage. This is characterized by neurite blebbing and fragmentation, and a reduction in the number of myelinated axons. However, this significant toxic effect of SSM5 was not observed in earlier cultures at the beginning of myelination. Anti-GluN1 AABs induce neurodegenerative changes and associated myelin loss in myelinated spinal cord cultures. These findings may point to the higher vulnerability of myelinated neurons towards interference in glutamatergic communication, and may refer to the disturbance of the NMDAR-mediated oligodendrocyte metabolic supply. Our work contributes to the understanding of the emerging association of NMDAR encephalitis with demyelinating disorders.https://www.mdpi.com/1422-0067/24/1/248anti-NMDARGluN1myelinated culturesNRHypodegeneration |
| spellingShingle | Mercedeh Farhat Sabet Sumanta Barman Mathias Beller Sven G. Meuth Nico Melzer Orhan Aktas Norbert Goebels Tim Prozorovski Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity International Journal of Molecular Sciences anti-NMDAR GluN1 myelinated cultures NRHypo degeneration |
| title | Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity |
| title_full | Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity |
| title_fullStr | Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity |
| title_full_unstemmed | Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity |
| title_short | Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity |
| title_sort | myelinating co culture as a model to study anti nmdar neurotoxicity |
| topic | anti-NMDAR GluN1 myelinated cultures NRHypo degeneration |
| url | https://www.mdpi.com/1422-0067/24/1/248 |
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