Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination
Abstract Progressive neurological decline in multiple sclerosis is associated with axonal loss and synaptic dysfunction in the non-demyelinated normal appearing gray matter (NAGM) and prominently in the cerebellum. In contrast to early disease stages, where synaptic and neuro-axonal pathology correl...
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| Format: | Article |
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BMC
2025-02-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | https://doi.org/10.1186/s12974-025-03368-9 |
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| author | Melanie Lohrberg Lena Sünke Mortensen Carolina Thomas Franziska Fries Franziska van der Meer Alexander Götz Carolin Landt Hong Jun Rhee JeongSeop Rhee David Gómez-Varela Manuela Schmidt Wiebke Möbius Torben Ruhwedel Luis A. Pardo Linus Remling Nadine Kramann Claudia Wrzos Erik Bahn Christine Stadelmann Alonso Barrantes-Freer |
| author_facet | Melanie Lohrberg Lena Sünke Mortensen Carolina Thomas Franziska Fries Franziska van der Meer Alexander Götz Carolin Landt Hong Jun Rhee JeongSeop Rhee David Gómez-Varela Manuela Schmidt Wiebke Möbius Torben Ruhwedel Luis A. Pardo Linus Remling Nadine Kramann Claudia Wrzos Erik Bahn Christine Stadelmann Alonso Barrantes-Freer |
| author_sort | Melanie Lohrberg |
| collection | DOAJ |
| description | Abstract Progressive neurological decline in multiple sclerosis is associated with axonal loss and synaptic dysfunction in the non-demyelinated normal appearing gray matter (NAGM) and prominently in the cerebellum. In contrast to early disease stages, where synaptic and neuro-axonal pathology correlates with the extent of T cell infiltration, a prominent role of the innate immune system has been proposed for progressive MS. However, the specific contribution of microglia and astrocytes to synaptic cerebellar pathology in the NAGM– independent of an adaptive T cell response - remains largely unexplored. In the present study, we quantified synaptic changes in the cerebellar NAGM distant from demyelinated lesions in a mouse model of toxic demyelination. Proteomic analysis of the cerebellar cortex revealed differential regulation of synaptic and glutamate transport proteins in the absence of evident structural synaptic pathology or local gray matter demyelination. At the functional level, synaptic changes manifested as a reduction in frequency-dependent facilitation at the parallel fiber– Purkinje cell synapse. Further, deficiency of MyD88, an adaptor protein of the innate immune response, associated with a functional recovery in facilitation, reduced changes in the differential expression of synaptic and glutamate transport proteins, and reduced transcription levels of inflammatory cytokines. Nevertheless, the characteristics of demyelinating lesions and their associated cellular response were similar to wild type animals. Our work brings forward an experimental paradigm mimicking the diffuse synaptic pathology independent of demyelination in late stage MS and highlights the complex regulation of synaptic pathology in the cerebellar NAGM. Moreover, our findings suggest a role of astrocytes, in particular Bergmann glia, as key cellular determinants of cerebellar synaptic dysfunction. |
| format | Article |
| id | doaj-art-6df37528be7d4dd7ab49742588fb0fb2 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-6df37528be7d4dd7ab49742588fb0fb22025-08-20T02:16:45ZengBMCJournal of Neuroinflammation1742-20942025-02-0122111710.1186/s12974-025-03368-9Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelinationMelanie Lohrberg0Lena Sünke Mortensen1Carolina Thomas2Franziska Fries3Franziska van der Meer4Alexander Götz5Carolin Landt6Hong Jun Rhee7JeongSeop Rhee8David Gómez-Varela9Manuela Schmidt10Wiebke Möbius11Torben Ruhwedel12Luis A. Pardo13Linus Remling14Nadine Kramann15Claudia Wrzos16Erik Bahn17Christine Stadelmann18Alonso Barrantes-Freer19Department of Neuropathology, University Medical Center GöttingenInterdisciplinary Center for Bioinformatics (IZBI), University of LeipzigDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Molecular Neurobiology, Max-Planck Institute for Multidisciplinary SciencesDepartment of Molecular Neurobiology, Max-Planck Institute for Multidisciplinary SciencesDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of ViennaDivision of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of ViennaDepartment of Neurogenetics, Max-Planck Institute for Multidisciplinary SciencesDepartment of Neurogenetics, Max-Planck Institute for Multidisciplinary SciencesOncophysiology Group, Max-Planck Institute for Multidisciplinary SciencesDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenDepartment of Neuropathology, University Medical Center GöttingenAbstract Progressive neurological decline in multiple sclerosis is associated with axonal loss and synaptic dysfunction in the non-demyelinated normal appearing gray matter (NAGM) and prominently in the cerebellum. In contrast to early disease stages, where synaptic and neuro-axonal pathology correlates with the extent of T cell infiltration, a prominent role of the innate immune system has been proposed for progressive MS. However, the specific contribution of microglia and astrocytes to synaptic cerebellar pathology in the NAGM– independent of an adaptive T cell response - remains largely unexplored. In the present study, we quantified synaptic changes in the cerebellar NAGM distant from demyelinated lesions in a mouse model of toxic demyelination. Proteomic analysis of the cerebellar cortex revealed differential regulation of synaptic and glutamate transport proteins in the absence of evident structural synaptic pathology or local gray matter demyelination. At the functional level, synaptic changes manifested as a reduction in frequency-dependent facilitation at the parallel fiber– Purkinje cell synapse. Further, deficiency of MyD88, an adaptor protein of the innate immune response, associated with a functional recovery in facilitation, reduced changes in the differential expression of synaptic and glutamate transport proteins, and reduced transcription levels of inflammatory cytokines. Nevertheless, the characteristics of demyelinating lesions and their associated cellular response were similar to wild type animals. Our work brings forward an experimental paradigm mimicking the diffuse synaptic pathology independent of demyelination in late stage MS and highlights the complex regulation of synaptic pathology in the cerebellar NAGM. Moreover, our findings suggest a role of astrocytes, in particular Bergmann glia, as key cellular determinants of cerebellar synaptic dysfunction.https://doi.org/10.1186/s12974-025-03368-9 |
| spellingShingle | Melanie Lohrberg Lena Sünke Mortensen Carolina Thomas Franziska Fries Franziska van der Meer Alexander Götz Carolin Landt Hong Jun Rhee JeongSeop Rhee David Gómez-Varela Manuela Schmidt Wiebke Möbius Torben Ruhwedel Luis A. Pardo Linus Remling Nadine Kramann Claudia Wrzos Erik Bahn Christine Stadelmann Alonso Barrantes-Freer Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination Journal of Neuroinflammation |
| title | Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination |
| title_full | Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination |
| title_fullStr | Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination |
| title_full_unstemmed | Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination |
| title_short | Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination |
| title_sort | astroglial modulation of synaptic function in the non demyelinated cerebellar cortex is dependent on myd88 signaling in a model of toxic demyelination |
| url | https://doi.org/10.1186/s12974-025-03368-9 |
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