Research Spotlight: How inflammation damages synapses in an experimental model of multiple sclerosis

Rebecca Gillani, MD, PhD, a physician investigator in the Department of Neurology at Massachusetts General Hospital and an Instructor in Neurology at Harvard Medical School, is the lead author of a recently published paper in Brain, Behavior, and Immunity; Instability of Excitatory Synapses in Experimental Autoimmune Encephalomyelitis and the Outcome for Excitatory Circuit Inputs To Individual Cortical Neurons.

What Question Were You Investigating?

The most obvious symptoms in many people with the inflammatory neurologic condition multiple sclerosis (MS) are the physical ones, including weakness and difficulty walking.

Still, the majority of people living with MS also struggle with disabling cognitive difficulties and profound fatigue. Cognitive difficulties are a major cause of decreased quality of life, loss of employment, and financial stressors in people living with MS.

It is well-recognized that in MS, inflammation attacks the protective myelin coating of nerve fibers, causing attacks of neurologic symptoms.

Now, it is also becoming clear that inflammation in MS is also widely destructive throughout the brain to whole brain cells (neurons) and their connections (called synapses).

Synapses are the site of information transmission and memory storage in the brain, and thus, inflammatory damage to synapses is a critical contributor to MS-related cognitive difficulties.

In this study, we investigate how inflammation damages synapses in an experimental model of MS.

What Methods or Approach Did You Use?

Synapses are not fixed structures; they constantly change as the brain learns and responds to the environment. We used an experimental model of MS and sophisticated multiphoton imaging technology to determine how synapses are shaped over time in the setting of inflammation in the brain.

Mice received intracranial injections to label neurons and excitatory synapses with fluorescent proteins. We obtained images of individual neurons and their populations of hundreds of synapses in living mice.

We observed how these synapses changed over time as the brain was attacked by inflammation.

We then examined brain tissue samples from these mice using a state-of-the-art method of super-resolution imaging that enabled us to view the structure of these tiny synapses and assess for synaptic damage and loss.

What Did You Find?

We discovered that excitatory synapses are destabilized by inflammation in the brain. While there is a constant turnover of synapses in the healthy brain, inflammation accelerated this turnover so that synapses were gained and lost at higher rates. This instability was widespread, impacting the entire neuron and leading to important changes in the incoming inputs to individual neurons.

When we examined brain tissue and synapses at super-resolution, we discovered that a small proportion of excitatory synapses were lost in neuroinflammation.

Thus, early inflammation in the brain destabilizes excitatory synapses, but they are not yet lost on a large scale.

What are the Implications?

The normal turnover of synapses in the healthy brain is critical for learning and memory. The instability and increased turnover of synapses and synaptic damage due to inflammation are likely an important cause of cognitive difficulties in people with MS.

Thus, synaptic damage is an important target for neurorestorative or neuroprotective therapies in people with MS—in particular, for therapies that aim to treat cognitive difficulties.

The ultimate goal is to develop therapies to preserve and restore neurologic function in people with MS.

What are the Next Steps?

Our next steps are to determine how this synaptic damage due to inflammation alters the activity of neurons. We also aim to identify what inflammatory substances and immune cells cause this synaptic damage to identify potential therapeutic targets.