No Neuron is an Island

An exosome taken up by a neuron.

An exosome (green) taken up by a neuron (red). Cell nucleus stained blue.

No neuron is an island. It comes as no surprise that the cells that are responsible for something as profound as our thoughts, feelings and movements require a lot of support and nurture. Neurons are supported and protected by cells known as ‘glial cells’. Glial cells have many functions, including but not limited to helping maintain a constant environment for neurons, and forming ‘myelin’, an insulating material that wraps itself around the neuron. Myelin insulation is similar to the insulating rubber that is wrapped around the copper wire inside an electrical cable. Optimal brain function depends on glial cells and neurons communicating with each other. But how does this happen at the molecular level? How do the neurons and the glial cells ‘talk’to each other, and what is their ‘language’? In a fascinating study, published in the Open Access journal PLOS Biology, researchers in Germany find tantalizing answers to just these questions.

Before we go through their findings, it is worth familiarizing ourselves with some basic neuroscience terms:

An action potential is the electrochemical method by which neurons carry messages, when electrically charged ions such as sodium or potassium (Na+ or K+) move across the cell membrane of a neuron. Therefore, by adding potassium to neurons growing on a petri-dish, we can artificially simulate neuronal activity. Glial cells are non-neuronal cells that support neurons. There are many different types of glial cells, and the main type we encounter in this study are “oligodendrocytes”. Although the name sounds long and complex, their function is simple; they form the myelin sheath that insulates neurons from the environment and from each other. Oligodendrocytes also frequently release vesicles known as exosomes; think of them as small bubbles containing various molecules such as proteins and RNA. These exosomes have the ability to affect neighboring cells, for both good and bad; contributing to immune response, yet sometimes aiding the spread of pathogens such as viruses. However, in this study they are implicated in cell communication, which is a brand new function for exosomes! In this study, the researchers looked at how exosomes aid in the communication between neurons and their support crew, the oligodendrocytes cells.First, the researchers confirmed that these molecular bubbles known as exosomes are indeed present inside oligodendrocytes. In science it’s always good practice to confirm known observations before venturing into the unknown. In the image below (you may want to click to enlarge!), you can see the cross-section of a neuron with layers of myelin from the oligodendrocyte wrapped around it like filo pastry surrounding a sausage roll. The image also highlights the exosomes, waiting to spill their contents into the vicinity of the neuron!

Mouse neuron

Electron micrograph of a cross section of a mouse neuron, showing myelin sheath wrapped around it. Enlarged inset shows a group of exosomes fusing with the neuron. Image credit: Eva-Maria Krämer-Albers

Next, they wondered what causes the exosomes to be released from the oligodendrocytes. Previous work had shown that the level of calcium ions (Ca2+) inside the oligodendrocyte stimulates exosome release, and it is also known that neurotransmitting molecules such as glutamate in the surrounding environment can affect Ca2+ signaling. Nerve impulses trigger glutamate release from neurons. By putting two and two together, the researchers set up an experiment where they grew oligodendrocytes in the presence and absence of glutamate and measured the release of exosomes. They also used a chemical that removes Ca2+, to check if Ca2+ was necessary for this process. Their results show that glutamate, released from active neurons, triggers Ca2+ dependent exosome release from oligodendrocytes.

The Boyden Chamber

The Boyden Chamber. Neurons are grown in the upper chamber, oligodendrocytes in lower chamber, allowing molecules to diffuse freely between the two wells. Image credit: Eva-Maria Krämer-Albers

The researchers then questioned whether neuronal activity is linked to the release of exosomes. They investigated this using an elegant set-up consisting of a Boyden Chamber (see Figure on left). The Boyden Chamber allows two different cell types to be grown in layers next to each other without them physically touching, yet permitting molecules released by the cells to diffuse across the layer boundary. The neurons were on top, the oligodendrocytes were below. The potassium ion concentration surrounding a neuron is important for its electrical activity. So the researchers added potassium to the neurons, to stimulate electrical activity and found that it was indeed sufficient to increase the release of exosomes from the oligodendrocytes below. Therefore, they conclude that exosome release by the oligodendrocytes is linked to neuronal activity.

What happens to these released exosomes? Researchers used fluorescent-labeled exosomes and watched what happens in neurons grown in petri dishes. They saw that neurons take up the exosomes, and the payload is effectively delivered. In this fantastic image below, the neuron is red, and the exosome is highlighted in green. Since this by itself was not sufficient proof, they also showed exosome transfer to neurons in mice brains as well.

How do these exosomes help neurons? As I mentioned previously, exosomes carry various molecules such as proteins and RNA. Again, the researchers used the Boyden Chamber to carry out an experiment to see how the neurons can benefit from the exosomes. Under optimal conditions, the exosomes don’t do much. However, if the neurons are damaged or stressed or starved of nutrients, then they function much better when exosome-secreting oligodendrocytes are present.

These findings are amazing, because it shows that these exosomes support neurons under conditions of cell stress, suggesting that they have a role in neuroprotection. The cell communication works both ways, because the neurons communicate with the oligodendrocytes (neurons release glutamate, making the oligodendrocytes release exosomes), and the oligodendrocytes communicate with the neurons by producing these neuroprotective care-packages, the exosomes, to soothe damaged and tired neurons! Neurons that have access to these exosomes are less sensitive to the damaging effects of stress and starvation.

Oligodendrocytes were long thought to provide just insulation for neurons. This work shows that they do more than that, and play an active role in supporting our hard-working neurons, by delivering a molecular care package. As we understand more about the complex relationship between nerve cells and the cells that nurture them, we are better able to understand what happens when things go wrong, be it brain damage or neurodegenerative diseases too.

Article Source: Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication
Frühbeis C, Fröhlich D, Kuo WP, Amphornrat J, Thilemann S, et al. (2013) Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication. PLoS Biol 11(7): e1001604. doi: 10.1371/journal.pbio.1001604

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