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Updated: Nov 2, 2025
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Acute and chronic synaptic pathology in multiple sclerosis gray matter
Marco Vercellino1, Stella Marasciulo2, Silvia Grifoni3
1I Division of Neurology and Multiple Sclerosis Center, Department of Neurosciences and Mental Health, AOU Città della Salute e della Scienza di Torino, Turin, Italy.
Objectives:
To investigate the extent of synaptic loss, and the contribution of gray matter (GM) inflammation and demyelination to synaptic loss, in multiple sclerosis (MS) brain tissue.
Methods:
This study was performed on two different post-mortem series of MS and control brains, including deep GM and cortical GM. MS brain samples had been specifically selected for the presence of active demyelinating GM lesions. Over 1,000,000 individual synapses were identified and counted using confocal microscopy, and further characterized as glutamatergic/GABAergic. Synaptic counts were also correlated with neuronal/axonal loss.
Results:
Important synaptic loss was observed in active demyelinating GM lesions (-58.9%), while in chronic inactive GM lesions, synaptic density was only mildly reduced compared to adjacent non-lesional gray matter (NLGM) (-12.6%). Synaptic loss equally affected glutamatergic and GABAergic synapses. Diffuse synaptic loss was observed in MS NLGM compared to control GM (-21.2% overall).
Conclusion:
This study provides evidence, in MS brain tissue, of acute synaptic damage/loss during active GM inflammatory demyelination and of synaptic reorganization in chronically demyelinated GM, affecting equally glutamatergic and GABAergic synapses. Furthermore, this study provides a strong indication of widespread synaptic loss in MS NLGM also independently from focal GM demyelination.
Insights
Multiple sclerosis (MS) causes significant synaptic loss in gray matter (GM), especially during active inflammation. Synaptic damage occurs both within lesions and in unaffected areas, impacting both major synapse types.
Area of Science:
- Neuroscience
- Neuropathology
Background:
- Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system.
- Gray matter (GM) pathology, including inflammation and demyelination, significantly contributes to MS progression and disability.
Purpose of the Study:
- To quantify synaptic loss in multiple sclerosis (MS) brain tissue.
- To determine the role of gray matter (GM) inflammation and demyelination in synaptic loss.
- To differentiate synaptic changes in active versus chronic MS lesions and non-lesional GM.
Main Methods:
- Analysis of post-mortem brain tissue from MS patients and controls.
- Confocal microscopy used to identify and count over 1,000,000 synapses.
- Characterization of synapses as glutamatergic or GABAergic, correlated with neuronal/axonal loss.
Main Results:
- Significant synaptic loss (-58.9%) observed in active demyelinating GM lesions.
- Mild synaptic reduction (-12.6%) in chronic inactive GM lesions.
- Widespread synaptic loss (-21.2%) found in non-lesional GM of MS brains compared to controls.
Conclusions:
- Acute synaptic damage occurs during active inflammatory demyelination in MS.
- Synaptic reorganization is evident in chronically demyelinated GM.
- Synaptic loss in MS is widespread, affecting both lesional and non-lesional GM, and impacts glutamatergic and GABAergic synapses equally.
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