%0 Journal Article %T Alterations of the axon initial segment in multiple sclerosis grey matter %+ Institut du Cerveau = Paris Brain Institute (ICM) %+ Institut de biologie de l'ENS Paris (IBENS) %+ Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB %+ Virginia Commonwealth University (VCU) %+ Hunter Holmes McGuire Hospital [Richmond, VA, USA] %+ University Medical Center Göttingen (UMG) %+ CHU Pitié-Salpêtrière [AP-HP] %A Senol, Aysegul Dilsizoglu %A Pinto, Giulia %A Beau, Maxime %A Guillemot, Vincent %A Dupree, Jeffrey %A Stadelmann, Christine %A Ranft, Jonas %A Lubetzki, Catherine %A Davenne, Marc %Z This work was funded by INSERM (Institut national de la santé et de la recherche médicale) Paris Brain Institute—Institut du Cerveau et de la Moelle (ICM), fondation pour l’Aide à la Recherche sur la Sclérose En Plaques (ARSEP) grant (to M.D.), Prix Bouvet-Labruyer̀e—Fondation de France (to M.D.), as well as a Multiple Sclerosis International Federation (MSIF) McDonald fellowship and ARSEP travel grant fellowship (to A.D.S.). %< avec comité de lecture %@ 2632-1297 %J Brain Communications %I Oxford University Press on behalf of the Guarantors of Brain %V 4 %N 6 %P fcac284 %8 2022-12-01 %D 2022 %R 10.1093/braincomms/fcac284 %M 36451656 %K axon initial segment %K multiple sclerosis %K grey matter lesion %K neocortex %K cerebellum %Z Life Sciences [q-bio]Journal articles %X 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 analysed 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 increased only in pyramidal neurons of inactive demyelinated lesions, compared with normal appearing grey matter tissue. 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. %G English %2 https://pasteur.hal.science/pasteur-04096429/document %2 https://pasteur.hal.science/pasteur-04096429/file/fcac284.pdf %L pasteur-04096429 %U https://pasteur.hal.science/pasteur-04096429 %~ PASTEUR %~ ENS-PARIS %~ CNRS %~ APHP %~ ICM %~ PSL %~ SORBONNE-UNIVERSITE %~ SORBONNE-UNIV %~ SU-MEDECINE %~ SU-MED %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ ENS-PSL %~ SU-TI %~ ALLIANCE-SU %~ FRANCE-GENOMIQUE %~ BIOINFO_BIOSTAT_HUB