Multiple sclerosis: Immune cells silence neurons by removing synapses

January 26, 2021

Damage to the brain gray matter plays an important role in the progression of multiple sclerosis. This study now shows that such damage can be caused by inflammatory reactions that lead to loss of synapses, which impairs neural activity.

Multiple sclerosis (MS) is a chronic inflammatory disease that affects the central nervous system, in which nerve cells are attacked by the patient's own immune system. In many cases, the disease develops into a progressive form, which is characterized by a shift of pathology from the white matter to the gray matter, for instance to the cerebral cortex. This phase of the disease has so far been difficult to treat and its underlying causes are poorly understood. Now, a research team led by Martin Kerschensteiner, Director of the Institute for Clinical Neuroimmunology at LMU, in cooperation with Thomas Misgeld (Technical University of Munich) and Doron Merkler (University of Geneva), has shown in a mouse model that inflammation of the gray matter leads to a decrease in nerve-cell activity, owing to the (potentially reversible) destruction of synapses. "Targeted inhibition of specific types of immune cells can slow synapse damage down, and offers an interesting new therapeutic approach," Kerschensteiner explains.

Loss of synapses - the structures that serve as functional contacts between nerve cells - is an early indicator of damage to the cerebral cortex in cases of progressive MS. The researchers therefore suspected that the synapses are the key to the neuronal damage that ensues in this stage of the disease. With the aid of various imaging techniques, the team was able to demonstrate that such widespread loss of synapses can be reproduced in a mouse model of MS. Moreover, their observations revealed that synaptic spines are destroyed by a specific type of immune cells. "These immune cells preferentially eliminate spines, which contain high levels of calcium. We assume that the inflammation reaction itself triggers an influx of calcium, which destabilizes the spines," says Kerschensteiner. "These changes in late-stage MS are reminiscent of those that can also be observed during the early phases of neurodegeneration," Misgeld adds. 

The disruption of neuronal networks in the brain can be reversible

The activated immune cells primarily attack excitatory synapses, which are responsible for activating other nerve cells. As a consequence, the level of activity in neural networks decreases. "The nerve cells are effectively silenced," says Kerschensteiner. "However, much to our surprise, we discovered that this process is reversible in our model."

As soon as the inflammation is resolved, the normal number of synapses is restored and the neurons once again exhibit their normal patterns of activity. These results contrast with findings in patients with progressive MS, in whom the cerebral cortex is permanently damaged. "Presumably, the mechanisms responsible for recovery cannot come into effect in these patients, because the inflammation is chronic and remains unresolved," says neuropathologist Merkler. "In our model, we induced an acute inflammatory reaction, which is resolved within a few days."

New pharmaceutical agents might be able to specifically inhibit the activation of the immune cells responsible for synapse destruction and could therefore slow the progress of the disease. However, it is crucial that such inhibitors do not completely block the action of these cells, so that they can continue to carry out their essential functions. The authors of the study hope that this concept can help develop therapeutic approaches that will effectively curb the progression of MS.
-end-
Nature Neuroscience 2021

Ludwig-Maximilians-Universität München

Related Multiple Sclerosis Articles from Brightsurf:

New therapy improves treatment for multiple sclerosis
A new therapy that binds a cytokine to a blood protein shows potential in treating multiple sclerosis, and may even prevent it.

'Reelin' in a new treatment for multiple sclerosis
In an animal model of multiple sclerosis (MS), decreasing the amount of a protein made in the liver significantly protected against development of the disease's characteristic symptoms and promoted recovery in symptomatic animals, UTSW scientists report.

Not all multiple sclerosis-like diseases are alike
Scientists say some myelin-damaging disorders have a distinctive pathology that groups them into a unique disease entity.

New therapeutic options for multiple sclerosis in sight
Strategies for treating multiple sclerosis have so far focused primarily on T and B cells.

Diet has an impact on the multiple sclerosis disease course
The short-chain fatty acid propionic acid influences the intestine-mediated immune regulation in people with multiple sclerosis (MS).

The gut may be involved in the development of multiple sclerosis
It is incompletely understood which factors in patients with multiple sclerosis act as a trigger for the immune system to attack the brain and spinal cord.

Slowing the progression of multiple sclerosis
Over 77,000 Canadians are living with multiple sclerosis, a disease whose causes still remain unknown.

7T MRI offers new insights into multiple sclerosis
Investigators from Brigham and Women's Hospital have completed a new study using 7 Tesla (7T) MRI -- a far more powerful imaging technology -- to further examine LME in MS patients

How to improve multiple sclerosis therapy
Medications currently used to treat multiple sclerosis (MS) can merely reduce relapses during the initial relapsing-remitting phase.

Vaccinations not a risk factor for multiple sclerosis
Data from over 12,000 multiple sclerosis (MS) patients formed the basis of a study by the Technical University of Munich (TUM) which investigated the population's vaccination behavior in relation to MS.

Read More: Multiple Sclerosis News and Multiple Sclerosis Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.