Damage to gray matter in the brain plays an important role in the development of multiple sclerosis. This study now shows that such damage can be caused by inflammatory reactions that lead to loss of synapses, impairing nerve 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 immune system. In many cases, the disease develops into a gradual form characterized by a shift of pathology from white matter to gray matter, for example to the cerebral cortex. Treating this stage of the disease has been difficult so far and its underlying causes are not well understood. Now, a research team led by Martin Kirschensteiner, Director of the Institute for Clinical Neurological Immunology at LMU, in collaboration with Thomas Misgeld (Technical University of Munich) and Doron Merkler (University of Geneva), has shown in a mouse model that inflammation leads to gray matter decreased neuronal activity, due to the destruction of (Reversible) of synapses. Kerschensteiner explains, “Targeted inhibition of specific immune cell types could slow synaptic damage and provide an interesting new therapeutic method.”
Loss of synapses – the structures that act as functional contacts between neurons – is an early indicator of cerebral cortical damage in cases of progressive MS. So researchers suspected that synapses were key to the neurological damage that occurs at this stage of the disease. With the help of various imaging techniques, the team was able to demonstrate that such widespread loss of synapses could be reproduced in a mouse model of MS. Moreover, their observations revealed that the synaptic backbone is being destroyed by a specific type of immune cell. These immune cells preferentially eliminate spines that contain high levels of calcium. We hypothesize that the inflammatory reaction in and of itself triggers an influx of calcium, which destabilizes the spine, ”Kirschsteiner says.“ These changes in late-stage MS remind us of those that can also be observed during the early stages of MS. Neurodegeneration. ”
Disruption of neural networks in the brain can be reversible
The activated immune cells mainly attack the excitatory synapses, which are responsible for activating other neurons. As a result, the level of activity in the neural networks decreases. “Neurons are effectively silenced,” Kirchsteiner says. “However, to our much surprise, we discovered that this process is reversible in our model.”
Once the inflammation resolves, the normal number of synapses is restored and the nerve cells again show their normal activity patterns. These results contrast with results in patients with progressive MS, whose cerebral cortex was permanently damaged. “It is assumed that the mechanisms responsible for recovery cannot be implemented in these patients, because the inflammation is chronic and remains unresolved,” says neurologist Merkler. “In our model, we induced an acute inflammatory reaction, which resolved within a few days.”
New pharmaceutical agents may be specifically able to block the activation of immune cells responsible for destroying synapses, and so could slow disease progression. However, it is crucial that these inhibitors not completely block the functioning of these cells, so that they can continue to perform their basic functions. The study authors hope that this concept could aid the development of treatment approaches that would effectively limit the progression of MS.
Natural Neuroscience 2021
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