Can we help the brain repair itself in multiple sclerosis?

A new research project lead by Mohit Dubey at the Netherlands Institute for Neuroscience will investigate whether GABA, one of the brain’s major chemical messengers, could play a role in repairing damage caused by multiple sclerosis (MS). The researchers hope to discover whether influencing this signalling system could help the brain restore damaged myelin.

In multiple sclerosis, the immune system damages myelin: the protective layer surrounding nerve fibres. Without this protective coating, nerve cells have more difficulty communicating with each other. The brain can repair some of this damage by producing new myelin, a complex multi-cellular process known as remyelination. But this repair is often incomplete.

Why myelin does not repair itself completely is not entirely clear, but it may be a result of increased inflammation and impaired function of microglia cells. Microglia are immune cells of the brain that are critical for myelination and its repair. Stressed microglia in the demyelination can create a sustained inflamed environment that makes it harder for the lesion repair.

In a previous study using brain tissue from people with MS and a mouse model of the disease, the Maarten Kole lab, Ramaglia, and Dubey found that microglia can remove specific connections between nerve cells during myelin damage. These connections use GABA as a chemical messenger and are part of brain circuits in the hippocampus, a region important for learning and memory.1. But how such signalling impact sustained inflammation remained unknown.

More than a neurotransmitter?

The new project will focus on GABA, best known as a neurotransmitter that helps reduce activity in the brain. Several existing medicines influence GABA signalling and can, for example, be used to help manage symptoms such as muscle stiffness. But GABA may have another role as well.

“We know relatively little about what GABA signalling does within an MS lesion and how it relates to inflammation,” explains Dubey. “We want to understand whether influencing this system could create better conditions for the brain to repair lesion.” Rather than looking only at the symptoms of MS, the researchers therefore want to understand what is happening within damaged brain tissue itself.

From human brain tissue to experimental models

The project will combine different approaches. Together with the Netherlands Brain Bank, the researchers will study donated brain tissue from people with MS. They will compare different types of lesions, including areas where myelin is being damaged and areas where effectively or poorly repaired.
This provides a detailed picture of what happens in the human brain during MS. Experimental models will then allow the researchers to investigate these processes further and test what happens when cell type specific GABA signalling is altered.

Combining the two approaches is particularly valuable. Human tissue shows what actually happens during the disease, while experimental models make it possible to investigate cause and effect.

Helping the brain repair

Ultimately, the researchers want to understand whether GABA signalling can be used to promote remyelination.“ The brain already has an inherent capacity to repair myelin,” says Dubey. “The question is whether we can create an environment in which that repair can happen more effectively.”

An important advantage is that medicines that influence GABA signalling already exist. If the researchers discover that particular forms of GABA signalling can support repair, this could provide starting points for future research into whether existing treatments could be used more effectively. But that possibility still needs to be thoroughly investigated: first, the underlying biology needs to be understood.

The research project is funded by Stichting MS Research and will run for three years.

1. Ramaglia V, Dubey M, Malpede MA, Petersen N, Vries SI de, Ahmed SM et al. Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory. Acta Neuropathol 2021; : 1–25.