Multiple sclerosis (MS) is a chronic illness that affects the brain and spinal cord. In this disease, nerve cells are attacked by the patient’s immune system.
Often, the disease develops into a progressive form 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 been challenging to treat, and its underlying causes are poorly understood.
Now, scientists at TUM, in collaboration with Ludwig-Maximilians-Univeristät in Munich (LMU) and the University of Geneva, have shown that 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.
Scientists have shown that the cause is inflammatory responses that lead to synapse loss, reducing neuronal activity. Targeted inhibition of these immune cells could mitigate such synaptic damage and provide a promising therapeutic option for progressive multiple sclerosis.
Thomas Misgeld, Professor for Neuronal Cell Biology at TUM, said, “This finding could make it possible to curb synapse loss with certain anti-inflammatory measures.”
In progressive MS, loss of synapses is a primary symptom of damage to the cerebral cortex; thus, scientists suspected that the synapses are the key to the neuronal damage that ensues in this disease stage.
Using several imaging techniques, scientists determined that such widespread loss of synapses can be reproduced in a mouse model of MS. Their observations revealed that a specific type of immune cell destroys synaptic spines.
Kerschensteiner said, “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.”
Misgeld said, “These changes in late-stage MS are reminiscent of those that can also be observed during the early phases of neurodegeneration.”
“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.”
“However, much to our surprise, we discovered that this process is reversible in our model.”
Doron Merkler, a neuropathologist at the University of Geneva, said, “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 recovery mechanisms cannot affect these patients because the inflammation is chronic and remains unresolved. In our model, we induced an acute inflammatory reaction, which is resolved within a few days.”
- M. Jafari et al. Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation. Doi: 10.1038/s41593-020-00780-7