RT Journal Article
SR Electronic
T1 Alterations of the axon initial segment in multiple sclerosis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.07.483302
DO 10.1101/2022.03.07.483302
A1 Aysegul Dilsizoglu Senol
A1 Giulia Pinto
A1 Maxime Beau
A1 Vincent Guillemot
A1 Jeff L. Dupree
A1 Christine Stadelmann
A1 Jonas Ranft
A1 Catherine Lubetzki
A1 Marc Davenne
YR 2022
UL http://biorxiv.org/content/early/2022/03/07/2022.03.07.483302.abstract
AB 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 StatementThe authors have declared no competing interest.AISaxon initial segmentAnkGankyrinGAPaction potentialEAEexperimental allergic encephalomyelitisKvvoltage-gated potassium channelsLFBluxol fast blueMHCmajor histocompatibility complexMOGmyelin oligodendrocyte glycoproteinMSMultiple SclerosisNAGMnormal-appearing grey matterNavvoltage-gated sodium channelsPLPproteolipid protein