Alterations of the axon initial segment in multiple sclerosis grey matter

Area of Science:

• Neuroscience
• Neuropathology
• Multiple Sclerosis Research

Background:

• Grey matter damage significantly contributes to disability progression in multiple sclerosis (MS).
• Synaptic alterations and neuronal damage occur in MS lesions and normal-appearing grey matter.
• The axon initial segment (AIS) is critical for neuronal function, but its role in MS is unknown.

Purpose of the Study:

• To investigate alterations in the axon initial segment (AIS) in grey matter of multiple sclerosis (MS) patients.
• To analyze AIS length and position in neocortical pyramidal neurons and cerebellar Purkinje cells in MS.
• To determine if AIS changes in MS correlate with neuronal excitability.

Main Methods:

• Immunohistochemistry was used to analyze AIS in neocortical and cerebellar tissue from control and MS patients.
• AIS length and soma-AIS gap were measured in layer 5/6 pyramidal neurons and Purkinje cells.
• Computational modeling was employed to assess the impact of AIS changes on neuronal excitability.

Main Results:

• AIS length increased in pyramidal neurons within inactive demyelinated lesions compared to normal-appearing grey matter.
• An increased soma-AIS gap was observed in both neocortical pyramidal neurons and cerebellar Purkinje cells in active and inactive lesions.
• Computational models suggest the increased soma-AIS gap may enhance neuronal excitability.

Conclusions:

• This study reveals, for the first time, AIS alterations in both active and inactive grey matter lesions in multiple sclerosis.
• Changes in AIS position and length in the neocortex and cerebellum may impair neuronal function in MS.
• Identified AIS modifications offer potential insights into MS pathophysiology and neuronal dysfunction.