Synapses & MS: An interview with Dr. Ben Barres

Following last month's webcast, Promising MS Research to Repair, Protect and Restore the Nervous System, we sat down with Dr. Ben Barres, Professor and Chair of Neurobiology at Stanford University's School of Medicine, to explore the exciting research he and his team are doing in the area of nervous system repair.

Dr. Barres, would you tell us a little bit about the work you’re doing in nerve connections and the leads you’re following in this area?

My lab is focused on understanding the role of glial cells in the brain. There are two different types of glial cells: oligodendrocytes and astrocytes. Many of you may have learned that oligodendrocytes cover the nerve fibers with myelin, which is damaged by MS. But the astrocytes, in particular, are a very mysterious class of brain cell. Making up about 40% of cells in the brain, they’re large cells that each ensheath (or cover) thousands of synapses (points of contact through which a signal is transferred from one neuron to the next).

The questions we’re asking in my lab are: What do the astrocytes do normally? And what do they do in diseases like MS? This has been one of the longstanding mysteries in neurobiology. Up until this point, we haven’t known what nearly half of our cells in our brain do. We know that neurons form the neural circuits, but what is the role of astrocytes in this process?

One of the things my lab has done over the years is develop tools to get at this question. We’ve found ways to purify astrocytes from the brain, allowing us to study what neurons do by themselves, as well as what they need the astrocytes for. Through this research, we’ve found that the astrocytes are actually in the driver’s seat when it comes to controlling the formation of synapses – almost like an on/off switch. If you take away the astrocytes, the neurons fail to form synapses, which was a big surprise.

When I started working on this 20 years ago, everyone thought astrocytes were just passive support cells that were cleaning up after the neurons. What we know now is that not only are astrocytes controlling synapse formation, but they also control the strength of synapses once they’re formed and the elimination of synapses. And we think that by better understanding astrocytes, we’re going to learn much more about how synapses work and how to rebuild synapses after injury.

Now that we understand the role of astrocytes in healthy cells, can you tell us about what happens in MS?

In neurodegenerative diseases, including MS, newer studies have shown that in addition to white matter damage (demyelination) there is also grey matter damage, neuron cell bodies and synapses are actually degenerating as well. Initially the brain has the ability to rebuild myelin, and also lost synapses, but as the disease progresses the pace at which synapses degenerate may outpace the brain’s ability to repair lost synapses. At a certain point, some individuals move into the neurodegenerative phase, also known as secondary-progressive MS.

At this phase, axons degenerate – in part because they’re losing their myelin. But scientists are now realizing that synapses are also being lost at this time. And quite possibly these two processes are connected. If this is the case, we need medications that will not only rebuild myelin, but also prevent the loss of synapses or stimulate reformation of synapses. Therapies that block synapse loss may also block axon loss and help to promote remyelination. Our hope is that rebuilding synapses will rebuild the circuit and allow normal function of that circuit.

What work is your lab doing in this area?

We’ve done a lot of work in understanding how these synapses are being lost. It’s been known for a long time that in normal brain development there’s excess generation of synapses and that the excess synapses – those that are not needed, or are formed in the wrong place, or are too weak to function correctly – are pruned back through a process called synapse elimination.

A few years ago, while working on something unrelated, my lab inadvertently discovered that an immune system pathway known as the classical complement cascade, which wasn’t even thought to be normally operating in the brain, was actually highly activated in a normal developing brain right at synapses.

This was such an exciting discovery because the classical complement cascade is an important part of the immune system outside of the brain. It collects bacteria, unwanted debris and dead cells and allows them to be cleaned up by other immune cells, almost like a garbage collector. While this has been well studied in the immune system outside of the brain, nobody knew that this same “clean up” process also took place within the brain. We discovered that the complement pathway was getting rid of excess synapses in the developing brain in a similar manner.

In the normal brain, this whole process turns off after synapse development is over. But in neurodegenerative diseases like MS or Alzheimer’s, this pathway turns on again and begins to kill off the synapses. Something happens to cause the complement cascade to inaccurately recognize healthy synapses as unhealthy and attack them. That makes the complement cascade a very attractive target – if we can develop therapies that target this pathway, we can potentially inhibit it and prevent the loss of nerve connections.

We need to do much more work to confirm this, but I’m very suspicious that this process is controlling the conversion from relapsing-remitting MS to the secondary-progressive phase of the disease. You need synaptic connections for axons to stay healthy. When the synapses start to die, the axons start to die as well.

If this hypothesis is true, what could this mean for people with MS?

In every phase of the disease synapses are being lost and this is a new way of thinking about the disease and approaching treatment. People have been so focused on the immune system and myelin, but this work would suggest that we need to also look at ways to block the synapse degeneration part of the disease.

While this work is primarily focused on stopping disease progression, the brain has tremendous capacity to repair itself. Even though targeting the complement system isn’t going to block the initial cause of the disease, it could be therapeutic in preventing progression and allowing the brain more leeway to repair itself.

How does nerve regeneration relate to all of this?

In the progressive phase of the disease, when axons are lost you have a problem. Because you no longer have a circuit, there’s nothing to myelinate. That’s when you start to see progressive dysfunction. One ideal approach to therapy would be to block degeneration on the front end, but many people have already experienced nerve degeneration and would like to have some repair of their neurological function. What we need to do for these people is to find a way to get their axons to regenerate. This has traditionally been a stumbling block on the part of neuroscience. There has been a lot of progress in the past 20 to 30 years to step-by-step dismantle this problem. And in just the last five years, there have been some really exciting steps forward. In fact we’re now able to get axons to regenerate in animal models with spinal cord injuries.

For people with any neurological injury, axon loss is invariably part of the injury. So far, scientists have only been able to get axons to regrow in the optic nerves – an area of the brain involving vision that can play a significant role in MS. Now scientists are working to get axons to regrow in the spinal cord and other parts of the brain. They’re also working to understand when axons regrow in the brain whether or not they will make the correct synaptic connections needed to accurately rebuild neural circuits. There have been exciting discoveries in this area in the last year, with research showing amazing capacity for these axons to extend and find their way back to the right place in the brain. More research needs to be done in this area, but I think this is going to lead to huge medical breakthroughs in restoring vision.

Is there anything else you would you like people with MS to know about the research that is going on in this area and what it means for them?

There’s never been a time in the history of mankind when scientific research progress has been so rapid. And in particular, the application of that research progress to disease treatment. These basic science discoveries are being converted into new treatments that are going into the clinic and being tested at an unprecedented rate. I think there is tremendous hope that new therapies are going to be generated in the next several years that will be very helpful to people with MS and other diseases.
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