Science Spin September 2008

Glial cells: Part of what makes the human brain special

By Marie-Catherine Mousseau

Most people see the brain as a gelatinous mass made of neurons, i.e. particular cells with the specific properties of communicating with each other via electrical signals. This is not totally wrong - the brain is gelatinous and contains as many as 100 billion neurons - a number of the same magnitude as the number of stars in our galaxy, or the number of galaxies in the universe. Many people, however, may not be aware it also contains close to ten times more of another cell type, not neurons. And the evidence increasingly shows that these other brain cells are at least as important as neurons in giving our brain the amazing properties it has.

These are called glial cells. "For every neuron in the brain there are 8 to 10 glial cells that are around each neuron," said neuroscientist and glial cell expert Dr Susanna Lyons, Assistant Professor at the University of Alabama. "Neurons represent only 10 to15 percent of the cellular space in the brain; glial cells, by contrast, represent 70 to 80 percent," she added.

So why is it that all of us know about neurons, but very few have heard about glial cells?

Neuroimmunology

Dr Lyons, came to Dublin to attend the International Neuroimmunology Symposium held at UCD in March this year. With more than 250 participants from Ireland and around the world, this symposium on neuroimmunology was a first in Ireland. Its success is partly due to PhD students from the UCD Marie Curie Programme in Molecular Immunology who organised it under the supervision of UCD lecturers Dr Clare O'Connor and Dr Antonio Campos-Torres.

Neuroimmunology is an emerging field combining neuroscience and immunology (study of the immune system), and this new field has very much to do with glial cells. Indeed, while neurons are the messengers taking care of the rapid transfer of information, glial cells are the soldiers posted all around, ensuring the transfer goes smoothly and fighting in case of aggression - that is their immune role

"Glial cells have been in the background because the neuronal connections were what people focused on," Dr Lyons explained. "But if you look at the synapses between two neurons where the communication is taking place, you'll see a glial cell right around that synapse listening and responding to that communication," she continued. "Part of that glial cell is connected to that circulatory system in the brain, and is also connected to other glial cells. This means one glial cell is talking to neurons, to the circulatory system and to the rest of the brain. Therefore if something goes wrong, if there is an injury, or an attack or a disease, glial cells are the first ones to respond."

She then added: "We feel, scientists who specialise in glial cells feel, that there can be no thought process without glial support; there can be no disease without glial participation."

Speaking at the Symposium, Professor Helmut Kettenmann, Professor of Cellular Neuroscience at the Max-Delbruck-Centrum, Berlin, and who has specialised in glial cells for almost 30 years, also acknowledges the critical importance of glial cells in brain functioning, inflammation and disease - an importance that he was among the first to recognise. "The classic neuroscientists and immunologists have been from originally completely different worlds. Classic neuroscience was looking at neuronal transmission and memory, and these immune-competent cells in the brain didn't get much attention for many years," he said. But now we know, as he put it, that "there is no disease where microglial cells" are not activated." Stroke, Multiple Sclerosis, Alzheimer's, Parkinson's disease, all seem to involve, at one stage or another, the participation of glial cells.

Good and Bad

STROKE

First of all, as Prof Kettenmann explained in his talk, microglial cells are essential elements for neuronal reorganization. In case of injury or lesion for instance - such as those following a stroke - microglial cells get activated and migrate to the ischemic area. Once there, they might act as house keepers, removing some neuronal inputs when they are no longer functional.

Prof Kettenmann has a hypothesis of how the system might work. In a normal brain there is a high level of neurotransmitters (signalling molecules involved in neuronal communication). Some of these would signal to glial cells that normal activity is going on and tell them to calm down. If there is an attack or an injury following a stroke, where there is neuron degeneration, less neurotransmitters would be produced; it would then become much easier for glial cells to get activated and play their cleaning role. This would explain why neurotransmitters in the brain seem to downregulate, rather than stimulate the activity of glial cells. "It is only a hypothesis but it would make a lot of sense," Prof Kettenmann said.

TUMOURS

But Prof Kettenmann also pointed out that glial cells are not always good. They may also have negative effects, for instance by facilitating brain tumour development. Prof Kettenmann indicated that in gliomas (brain tumours), near to one third of tumour mass is represented by microglial cells (note that we talk about gliomas, not neuromas - no wonder neurons can't make tumours as they cannot divide themselves) "When microglial cells are present we observe more migration of glioma in the brain", Prof Kettenmann said. He explained that microglial cells seem to release an enzyme that instruct tumour cells to get in a particular state which help them invade the brain.

Does it mean that a better understanding of glial cell involvement in brain tumour might lead to a potential cure? Not only that. Unfolding the immune role of glial cells might lead to new therapeutic approach for all disorders involving brain inflammation. The fact is, many brain diseases may be associated at the start with some glial cell dysfunction.

Alzheimer's, Schizophrenia, Parkinson's Disease

This could be the case for Alzheimer's. Prof Kettelmann published a review in Nature Neuroscience last December summarising the current understanding of the mechanisms underlying the development of the condition. "What came out is that there may be an early phase of Alzheimer's disease, prior to large deposits, where something immunological goes wrong which may start the whole cascade," he explained.
Schizophrenia is another candidate for the immune dysfunction hypothesis.

Also speaking at the symposium, Bartlomiej Lukasz, PhD student from the UCD Marie Curie Molecular Immunology programme, explained how his research based on animal models of schizophrenia showed the involvement of a few genes associated with the body's immune defence system. It seems that in the case of schizophrenia these 'immune-related genes' are not expressed to the same level. "Our findings suggest that disruption of specific immune response systems can play an important role during schizophrenia development," Bartlomiej concluded.

In the development of Parkinson's disease also, immune processes and glial cell functioning might play an important role. Presenting her results at the symposium, Catriona Long, PhD student at UCC, pointed out that activated microglial cells are observed in Parkinson's models, in particular in the area rich in dopamine neurons (Substantia Nigra) - which is the one that is destroyed in the disease process. At the same time, high levels of cytokines (immune molecules) were found in the same area of Parkinson's patients. Are these immune molecules a cause or a consequence of the disease?

Their finding rather points towards a cause. When they used a toxin to trigger the release of one of the immune factors involved, the result was more dopamine neurones destroyed! So it appears that they identified some immune molecule which acts as a death mediator on dopamine neurons - that is a potential trigger or accelerator of Parkinson's disease.

Trigger

However, as Prof Kettelmann put it, we cannot jump to conclusions. "This research just looks at one aspect of the disease by only studying cultures of brain cells," he said. One thing we know for sure is that microglial cells are activated in the region where neurons degenerate, but the question is - is it an initial trigger? "What's happening in the whole brain of a Parkinson's patient that triggers the condition is still very much a mystery," Prof Kettelmann commented.

This is also true for Alzheimer's disease, where the role of glial cells is not all that clear.

According to Prof Kettelmann, while some glial cell dysfunction might start the development of the disease, it becomes obvious that later on microglial cells help to fight it because they increase their phagocytic activity on plaques (i.e. engulf deposits that are characteristic of Alzheimer's).

The same uncertainty also applies for multiple sclerosis, an autoimmune disease characterised by an inflammation of the brain. "In Multiple Sclerosis we know that microglial cells are activated and produce a lot of inflammatory molecules, but we don't know if it causes the disease or if it is a consequence," Prof Kettenmann said. "What is the trigger of the inflammation?"

Taking a more general stance he concluded: "for each brain disease - i.e. schizophrenia, depression, MS, Alzheimer's - essentially we do not know what starts it from the very beginning. While for all brain diseases microglial cells are activated, the question remains - is it just a response, or is it part of the ongoing pathological process?"

So it looks like that there is still a long way to go to understand why things go wrong, especially as we first need to understand what's happening when the brain does function properly. On the bright side, our understanding seems to improve at an accelerated pace. "The advances in the last 10 years have been amazing; with all the new technologies such as in-vivo (cellular) imaging, we're getting much closer to good animal models and no longer only rely on cell lines and cell cultures," said Prof Helmut Kettelmann. Not to mention techniques such as brain scans - "the big imaging" as he called it - which allow us to look directly into the brain and watch how cells interact.

Combined together, these new techniques have the potential to unfold the mysterious role of those neglected components that make up most of our brain. The answer to this puzzle is even more critical since we realised that glial cells seem to play a key part in the evolution of the brain. Indeed, evidence shows that they increased in proportion as vertebrates evolved.

"While there is the same amount of glial cells and neurons in lower vertebrate, in humans there are many, many more glial cells than neurons," saidDr Campos-Torres. "In fact, the evolution of brain function matches with the increased number of glial cells - not so much with the increased number of neurons," he continues. And interestingly, Einstein's brain was found to have much more glial cells than the average brain! "This actually supports the idea that glial cells might play a fundamental role in modulating higher cognitive function," Antonio comments.

So perhaps understanding glial cell functioning may well shed some light on what's so special in our brain that makes us human.

 

DIFFERENT TYPES

Microglial cells are one of the three types of glial cells. The other types are astrocytes and oligodendrocytes. Microglial cells are also the ones that are better known to be involved in the immune regulation of the brain (their embryonic origin is actually different from that of neurons, and similar to that of other immune cells in the body).

 

The happy marriage of neuroscience and immunology
HOW IT ALL STARTED

There used to be Neuroscience on one hand and Immunology on the other. From their union an offspring was born: Neuroimmunology. Or more precisely the first Neuroimmunology post-graduate programme in Ireland. So here is the story of how a new field in science was formed.

Dr Clare O'Connor is an immunologist. This means she studies the way the immune system works in the body, including allergies, resistance to disease, and acceptance or rejection of foreign tissue. She also had research ideas involving the immune system and the brain including the development of brain diseases such as Alzheimer's. However, investigating the brain comes under a totally different discipline with its own set of rules and expertise that is neuroscience. And there was a time Clare had no neuroscientist to help her deal with the brain aspects.

Things all changed when the Conway Institute in UCD was formed. "Very early on when the Conway was up, new people were coming from different areas, one neuroscience and one immunology," she explained. And like her, some people were thinking of research that they would love to do involving both disciplines - this would come under the appellation of Neuroimmunology.

The idea was born. "The concept we had of neuroimmunology was not just the immunology of neurodegenerative disease; it was how the immune and the nervous systems interact in the brain and also in the rest of the body," Dr Clare O'Connor explained. According to her, a lot of people were interested, but the focus wasn't there yet.

Neuroimmunology programme

Then this opportunity came up to set up a Neuroimmunology programme as part of an EU programme for the training of PhD students. "Clare's idea was to go for it. She felt it was a very good area, a good topic, a research that is very favoured at the moment, very topical," said Dr John O'Connor, Head of the UCD Undergraduate Neuroscience Programme, representing the neuroscience side. "So Clare and I got together with neuroscientists and immunologists at the Conway Institute to discuss the possibility of submitting a grant."

The chances of getting it, however, were very low. "It's quite prestigious to get one. Of all the applicants coming in, only 5 percent would get funded by the European Union," Dr John O'Connor pointed out. But they got it, and he explains the reasons for their success: "the science is only one part, the proposal had a very strong component of what we would do with the students, how we would train them," he says. "The EU saw it as exactly what they wanted for a training site," Students seemed to find it attractive as well - "we had lots of applicants, so our problem was to pull it down," Dr Clare O'Connor said..
To date one of the great achievements of the PhD students who were accepted in the Marie Curie Programme was to organise the International Neuroimmunology Symposium -- a first in Ireland. This achievement was made possible thanks to the close supervision of Dr Clare O'Connor who became head of the programme and Dr Antonio Campos-Torres, lecturer at UCD and course coordinator of the programme.

Dr Campos-Torres had just arrived to work at UCD, when the programme was being put in place. "Clare gave me the great opportunity to be part of its organisation and together we created the post-graduate molecular neuroimmunology course," he says. "I was very enthusiastic to participate in this new programme. In my case to become a neuroimmunologist I had to train in neuroscience in France and then go to the USA to be trained in immunology," he explained. "At UCD the students have all in one."

A bright idea

Participants at the Symposium all welcomed the idea of a Neuroimmunology programme and acknowledged its success. "Putting neuro and immuno together is very good for the students - stimulates new ideas, people interaction,", saidProf Helmut Kettelmann.

Another speaker, Dr. Esther Sternberg of the NIH, Bethesda, USA, leading scientist in the area of mind-body interactions, comments: "I think the Neuroimmunology programme is an excellent, excellent idea and very important. One of the difficulties in academy is that there are sidewalls of different departments in different fields; so if you are a neuroscientist you are in the Department of Neuroscience, and if you are an immunologist you are in the Department of Immunology.

This means students don't get trained in interdisciplinary research; they learn the language of neuroscience or immunology and when they come out at the other end they can't necessarily collaborate with the researchers of the other disciplines." She continued: "That's why I think it's a wonderful thing to have a formal degree in neuroimmunology. From what Clare described there is a real interdisciplinary training between neuroscience and immunology and the conference certainly reflects that - the levels of the abstracts and posters were really outstanding."

The concept however is not totally new; it has been in the air for a while. "There have been groups such as the International Society of Neuroimmunology, the European Society of Neuroimmunology," Dr John O'Connor pointed out. Prof Kettelmann mentioned that last year their 'Students in Berlin Brain Days', organised by all PhD students in Berlin had neuroimmunology as the main topic. Dr Esther Sternberg also stated that the NIH started a similar kind of programme -- of which she is director. "But it s not a training programme and more a research programme," she notes. "In fact there hasn't been a training site like this put forward by the EU," Dr John O'Connor said.

Way to go

According to Dr Clare O'Connor, the next couple of years are going to be crucial: "We're half way through the programme. The next challenge is to build from what we have to ensure that in two years time it will continue. What I would like to see in the next two years: that the structure which we created now using the EU as a base will increase in terms of the number of people involved and the amount of research going on.".
So they planted the seeds, let's hope now Clare's wish will be fulfilled and the field of Neuroimmunology will blossom.