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Kole Group

Axonal signaling

About the Kole Group

The aim of our research is to unravel the functional properties of axonal signal conduction, and in particular to understand the dysfunction during demyelinating diseases such as multiple sclerosis.

There is still no treatment for MS (multiple sclerosis), a disease that is characterized by the degradation of myelin. The reason for this lack of treatment is that the mechanisms that underlie myelin degradation are still unclear. Painstaking research into electrical signals and interactions within nerve cells, and between nerve cells and myelin, could lead to a better understanding of this process.

Axons provide the wiring to connect neurons, and generate and conduct electrical impulses, which are the fundamental operations for fast electrical signaling and information storage in the nervous system. In order to enhance the speed of electrical transmission, axons are tightly wrapped by multiple layers of fatty layers, called myelin, derived from glia cell types. Although myelinated axons play pivotal roles in brain function, only little is understood about the precise electrical properties, their development or electrical architecture. Using advanced electrophysiological methods, high-resolution imaging and computational methods, our group studies signal conduction in the neocortical primary axon.

Maarten Kole:

‘In fact,’ says Maarten Kole, ‘you have a huge power plant between your ears.’ And you can almost hear the lines crackle when he explains this. We have over 80 billion nerve cells. These cells all communicate with each other through short bursts of electrical current called action potentials. The cells receive these bursts via dendrites, which look like branches on a tree. In their turn, the axons of these dendrites, which are a bit like the tree roots, send information to thousands of other cells.

Most cells only fire off an impulse once per second, but that does not go for the layer-5 cell that Kole is studying. This giant among brain cells fires no less than 4 times per second and is responsible for 60 percent of all the electrical impulses in our cortex whenever we see, hear or perceive something. Kole: ‘And don’t forget that there are tens of thousands of ion channels located within one single area at the start of every axon, and that these constantly renew themselves. It is quite astonishing really that you when you wake up in the morning you still have the same ideas as the day before. Although a brain cell is never a fixed entity, and despite this plasticity, your brains also have a certain degree of stability.’

Of all the features of this amazing world of the brain, what Kole is most intrigued by is myelin, the substance – or rather, the lack of it – that plays a central part in multiple sclerosis (MS). Kole: ‘The current view is that myelin is a fatty layer of insulation that wraps itself around the axons and ensures that conduction, and thus the exchange of information between nerve cells, is fast. But we think that there are more interspaces where an electrical current might run, both within the myelin and between myelin and nerve cells. And that is quite a revision of the current thinking.’

Kole is trying to measure what this might mean in terms of the way in which electrical conduction takes place and of the way in which action potentials move around exactly. A very complicated job: ‘Those layers of myelin and the cell membranes are sometimes only nanometres apart, and when you consider that one nanometre is one hundred thousand times smaller than the diameter of a hair…’ Kole was able to use a new technique for these measurements. Current is usually measured with amplifiers, but in Kole’s lab a technique has been developed where a fluorescent substance makes the current visible: ‘Like a current detector, where the degree of light intensity indicates what the difference in potential is across a cell membrane.’ It yielded a picture that was different from what he had expected: ‘I thought there would be a wave that ran on in a constant manner, but actually there were jumps in space and time; something that has never been seen before. That pattern also tells us something about the myelin: how well it insulates, whether this process is different from how we thought it was, and whether it insulates at all.’

During all that measuring and peering, Kole discovered that there are nanospaces within the myelin where he discovered, to his surprise, mitochondria, which are the power plants of a cell. The energy produced there by these mitochondria is used to make myelin. Kole: ‘Researchers had already found that a decreased energy production of mitochondria in nerve cells is related to myelin loss. Mitochondria within the myelin itself, the place where it is all happening, are probably of even greater importance for the repair of myelin after damage. We would therefore like to know the ins and outs of this process.’

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