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Alterations of the axon initial segment in multiple sclerosis

Aysegul Dilsizoglu Senol, Giulia Pinto, Maxime Beau, Vincent Guillemot, Jeff L. Dupree, Christine Stadelmann, Jonas Ranft, Catherine Lubetzki, View ORCID ProfileMarc Davenne
doi: https://doi.org/10.1101/2022.03.07.483302
Aysegul Dilsizoglu Senol
1Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
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Giulia Pinto
1Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
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Maxime Beau
3Institut de Biologie de l’École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, Inserm, PSL Research University, Paris, France
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Vincent Guillemot
1Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
4Institut Pasteur, Université de Paris, Bioinformatics and Biostatistics Hub, F-75015 Paris, France
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Jeff L. Dupree
5Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA
6Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA
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Christine Stadelmann
7Institute of Neuropathology, University Medical Center Göttingen, 37075 Göttingen, Germany
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Jonas Ranft
3Institut de Biologie de l’École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, Inserm, PSL Research University, Paris, France
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Catherine Lubetzki
1Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
2Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, DMU Neurosciences, Paris, France
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Marc Davenne
1Sorbonne Université, Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
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  • ORCID record for Marc Davenne
  • For correspondence: marc.davenne@sorbonne-universite.fr
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Abstract

Grey matter damage has been established as a key contributor to disability progression in multiple sclerosis. Aside from neuronal loss and axonal transections, which predominate in cortical demyelinated lesions, synaptic alterations have been detected in both demyelinated plaques and normal-appearing grey matter, resulting in functional neuronal damage. The axon initial segment is a key element of neuronal function, responsible for action potential initiation and maintenance of neuronal polarity. Despite several reports of profound axon initial segment alterations in different pathological models, among which experimental auto-immune encephalomyelitis, whether the axon initial segment is affected in multiple sclerosis is still unknown. Using immunohistochemistry, we analyzed axon initial segments from control and multiple sclerosis tissue, focusing on layer 5/6 pyramidal neurons in the neocortex and Purkinje cells in the cerebellum and performed analysis on the parameters known to control neuronal excitability, i.e., axon initial segment length and position. We found that the axon initial segment length was unchanged among the different multiple sclerosis samples, and not different from controls. In contrast, in both cell types, the axon initial segment position was altered, with an increased soma-axon initial segment gap, in both active and inactive demyelinated lesions. In addition, using a computational model, we show that this increased gap between soma and axon initial segment might increase neuronal excitability. Taken together, these results show for the first time changes of axon initial segments in multiple sclerosis, in active as well as inactive grey matter lesions in both neocortex and cerebellum, which might alter neuronal function.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    AIS
    axon initial segment
    AnkG
    ankyrinG
    AP
    action potential
    EAE
    experimental allergic encephalomyelitis
    Kv
    voltage-gated potassium channels
    LFB
    luxol fast blue
    MHC
    major histocompatibility complex
    MOG
    myelin oligodendrocyte glycoprotein
    MS
    Multiple Sclerosis
    NAGM
    normal-appearing grey matter
    Nav
    voltage-gated sodium channels
    PLP
    proteolipid protein
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    Posted March 07, 2022.
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    Alterations of the axon initial segment in multiple sclerosis
    Aysegul Dilsizoglu Senol, Giulia Pinto, Maxime Beau, Vincent Guillemot, Jeff L. Dupree, Christine Stadelmann, Jonas Ranft, Catherine Lubetzki, Marc Davenne
    bioRxiv 2022.03.07.483302; doi: https://doi.org/10.1101/2022.03.07.483302
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    Alterations of the axon initial segment in multiple sclerosis
    Aysegul Dilsizoglu Senol, Giulia Pinto, Maxime Beau, Vincent Guillemot, Jeff L. Dupree, Christine Stadelmann, Jonas Ranft, Catherine Lubetzki, Marc Davenne
    bioRxiv 2022.03.07.483302; doi: https://doi.org/10.1101/2022.03.07.483302

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