One example of the latter recently came from the joint laboratory of Freda Miller and David Kaplan, at the Hospital for Sick Children in Toronto. They found that a type of cell known for transmitting information between nerve cells also plays another vital role. It instructs stem cells that build the brain to make another type of cell called an oligodendrocyte. This cell is crucial for making sure communication and information transmission in the brain happen at the right time in the right place. The results were published in the journal, Neuron, http://www.cell.com/neuron/fulltext/S0896-6273(17)30344-6.
The team was looking at one particular type of cell, known as an inhibitory interneuron. It acts as a link between neurons and helps to develop the neural circuits we use every single second. As the name implies, the major function is to dampen electrical signals to ensure clarity of a single message from the body to the brain, and vice-versa. This allows us to learn, memorize, and carry out complex tasks.
Because of the important role of interneurons, any changes in their population number or ability to properly perform their duties during development can lead to trouble. Several chronic conditions have been attributed to issues with interneurons such as autism spectrum disorders, epilepsy, and mental health illnesses like schizophrenia.
The interneuron was the main focus of Miller’s team when they began the study. They wanted to find out if these cells have another function during brain development, aside from communicating with neurons. By analyzing them in real time, the group could learn more about what goes right and what could possibly go wrong.
The first step was to track interneurons during brain development. Unlike excitatory neurons, which form in the brain region they are intended to function, interneurons are formed in only a few areas of the brain. They then migrate over large distances to other regions where they align with neurons to form the proper circuitry. Miller’s team was examining a specific area known to be rich in migrating interneurons, the cortex.
In the cortex, the group expected to observe a normal interneuron integration process. Interneurons first would use chemicals to announce their arrival. The neurons would respond in kind to open up an appropriate space. The two would then come together and form a content circuit.
While this did happen, something far more interesting appeared to be occurring. When interneurons entered the developing cortex environment, they were found to mingle with stem cells that build the cortex. Moreover, when interneurons were removed from the developing cortex, they saw a drop in oligodendrocytes, cells that are responsible for producing the wrapping or insulation around the electrical conductor part of the neuron, ensuring rapid transfer of signals. Without oligodendrocytes, brain communications would be dramatically slowed and become unreliable.
The team went on the hunt to find out whether interneurons were prompting stem cells to become oligodendrocytes. There had to be something making this phenomenon occur and they were going to find it. But this had to be done systematically. That meant going in silico.
Rather than rely on cells, the team focused on computer programs to identify chemical signals that could be sent by interneurons and received by neural stem cells. Eventually, the data crunching revealed 51 molecules with the potential to invoke some type of change in neural stem cells.
Some of the names on the list were familiar. But one seemed a little out of place. It’s known as fractalkine. The molecule wasn’t new, however. Instead, it was its function that made its presence on the list a mystery.
Normally, fractalkine is considered to be a member of the immune system and its primary function is to regulate inflammation and ensuring a battle with infection is waged until victory. While this may be good in terms of infection, the molecule also has been implicated in a host of chronic diseases, including cardiovascular diseases, rheumatoid arthritis, inflammatory bowel disorder, and even neuropathic pain.
For Miller’s team, fractalkine would be the last molecule one might suspect in a list for normal brain development. For this reason, the team decided to find out what fractalkine was doing in this usually non-inflammatory environment. They used a variety of techniques to examine the function in the hopes of coming up with a concrete answer.
At the time, they had no idea what to expect. But when the results came back, the group was in a word, stunned. Indeed, fractalkine signalling was involved in the formation of oligodendrocytes from stem cells. But unbelievably, the molecule was necessary for proper brain development.
On its own, this discovery is destined to make waves. Not only did the researchers uncover a new function for inhibitory interneurons, but also reveal that the fractalkine apparently has an additional purpose in the brain. Neuroscience researchers will need to view both in a very different light now.
The results also suggest a path forward for treatment of diseases involving white matter damage, such as stroke and multiple sclerosis. If adding fractalkine to the injured will “wake up” brain stem cells and increase oligodendrocyte populations, this would then improve the chances for proper communication in the brain. Although this may be years down the road, the team’s discovery offers hope for those suffering from neurodegenerative illnesses that a treatment for repair may come.
Original research article:
Voronova A, Yuzwa SA, Wang BS, Zahr S, Syal C, Wang J, Kaplan DR, Miller FD. Migrating Interneurons Secrete Fractalkine to Promote Oligodendrocyte Formation
in the Developing Mammalian Brain. Neuron. 2017 May 3;94(3):500-516.e9. doi: 10.1016/j.neuron.2017.04.018.