Alterations of the axon initial segment in multiple sclerosis grey matter

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 increased only in pyramidal neurons of inactive demyelinated lesions, compared to 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.

Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

“…d Drawing representing an MN and its different regions of interest: the soma area, the GAP and the AIS along the proximal axonal region. The red dotted line indicates how the soma was delimitated in each neuron with concave lines crossing both sides of each neurite entry zone, as described previously [ 35 ]. e – k Graphs show the different quantifications done on images acquired in cultures of control, SOD1, C9orf72 and TARDBP MNs with or without pNF-M/H accumulations (Acc) (see “ Materials and methods ”): e soma areas, f – k length, mean axonal caliber and area of AIS ( f , g , h ) and GAP ( i , j , k ).…”

“…Only cells with a single soma-derived AIS were included in the quantitative analysis. To measure the length or area of the AIS and of the region between the soma and the AIS (the GAP), we used the methods described in Senol et al [ 35 ]. The MAP2 staining allowed us to delimitate the soma contour because MAP2 is a somato-dendritic marker that also stains the beginning of the axon (the GAP) with a decreased intensity (as seen on Fig.…”

Contribution of Axon Initial Segment Structure and Channels to Brain Pathology

“…A recent study on multiple sclerosis human tissue has shown that the gap between soma and AIS increases in pyramidal neurons and Purkinje cells in multiple sclerosis tissue and that the AIS is longer in cortical neurons of cortical inactive lesions [ 116 ]. Whether these AIS plasticity changes lead to voltage-gated ion channel expression or function alterations remains elusive, and further studies are necessary to decipher the potential role of the AIS in ALS and MS.…”

RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis

“…During the early stages of MS, the brain attempts to compensate for demyelination by redistributing voltage-gated Na + channels that were concentrated in the Ranvier nodes, along the axon; this allows for slow but effective nerve conduction (Dutta et al, 2006). Senol et al (2022) show that there are alterations in the initial segment of axons that could possibly lead to increased neural excitability, in both active and inactive lesions from patients.…”