We May Have Misunderstood Myelin
By: Ben L. Callif
Tags: Neuroscience, The Law Of The Instrument, Brain, Myelin, Biology

Myelin is often referred to as an insulator because it drastically increases the speed of action potential propagation; an axon ensheathed in myelin can send signals up to 300x faster than its unmyelinated counterparts. This enhanced conduction speed allows rapid communication to occur between distal parts of a spread out body plan. For example, a nerve impulse travels a great distance — from your foot to your brain and back to your foot — in a tiny fraction of a second. And this is a highly valuable feature of a living body — your chances of survival in dangerous situations depend largely on your reaction time. For this reason, myelin is a feature found in every vertebrate and may be an evolutionary requirement for the existence of vertebrates in general.

Myelin: More Than A Golden Insulator

Referring to myelin as an “insulating sheath” evokes an inaccurate equivalence between the brain and a modern electronic device, as if myelin is a piece of non-conductive material that wraps around an electrical wire. But myelin does so much more than function as an inert piece of insulation. As I mentioned before, the brain’s glial cells play the vital role of providing nutrients to power-hungry neurons. This is extremely important for oligodendrocytes because the insulating nature of myelin also isolates axons from the extracellular space. Whereas many types of cells can simply collect their own food from the environment, myelinated neurons have no access to the outside world. Oligodendrocytes are in the perfect position to spoon-feed neurons that constantly need to meet the energy demands of their firing axons.

Oligodendrocytes traffic RNA across microtubules (which are lit up in this GIF) to maintain myelin through local translation. They also transport energy substrates, like lactate, through myelin into actively firing axons. Image Credit: @Meng2fu

The importance of this this relationship between oligodendrocytes and neurons cannot be understated — proper myelination is absolutely necessary for our health. Evidence has linked abnormalities in myelin structure and function to a wide range of diseases. For example,

Multiple sclerosis is caused when the immune system selectively attacks and degrades myelin

is caused when the immune system selectively attacks and degrades myelin Cognitive disturbances in schizophrenia seem to be related to oligodendrocyte and myelin dysfunction

seem to be related to oligodendrocyte and myelin dysfunction Post-mortem observations have seen that people with major depression show changes in myelinated regions of the brain

show changes in myelinated regions of the brain Children with autism show an antibody response to myelin, which is similar to the etiology of multiple sclerosis

show an antibody response to myelin, which is similar to the etiology of multiple sclerosis Veterans with post-traumatic stress disorder (PTSD) actually show increased myelination in parts of the brain

Clearly, oligodendrocytes need to maintain a delicate balance of myelination to ensure neuronal health and brain function. Even beyond disease and dysfunction, myelination is a highly dynamic process that is constantly changing in response to the growth and behavior of an organism. For example, action potential conduction delays remain the same throughout development despite a huge increase in the distance that nerve impulses are required to travel (as the body gets bigger over time). In addition, extensive piano practice induces large-scale myelination changes in specific brain regions as a resulting of learning a new motor skill.

But how can oligodendrocytes respond so dynamically to the needs of individual axons, the growth of a body, and the behavior of an organism? It had been hypothesized that a form of rapid communication between neurons and oligodendrocytes must be maintained in order to support these dynamic and responsive changes in myelin structure. And indeed, such a structure was recently discovered underneath the many layers of the myelin sheath: a hidden synapse between an axon and its myelin.

The Axo-Myelinic Synapse

Synapses are considered to be the major form of information processing in the brain. They are defined by Oxford Lexico as “a junction between two nerve cells, consisting of a minute gap across which impulses pass by diffusion of a neurotransmitter.” But synapses aren’t found only between nerve cells. The evidence is mounting that axo-myelinic synapses are formed within every segment of myelin and its underlying axon. These synapses seem to work in exactly the same way as a synapse between two neurons: an action potential causes the fusion of vesicles with the cell membrane, which dumps the contents of the vesicles (neurotransmitters) into the synaptic cleft. Then, protein receptors on the post-synaptic neuron sense the incoming chemical signal and respond accordingly.

Action potentials induce the release of neurotransmitter at the synapse, which binds to post-synaptic receptors to induce a response in the receiving neuron. Image Credit: Wikimedia Commons

In the case of neuron-to-neuron synapses, neurotransmitters will sometimes induce an action potential in the post-synaptic cell. But this doesn’t really apply to axo-myelinic synapses, because oligodendrocytes don’t produce action potentials. However, there are many other downstream effects that occur when neurotransmitters bind to receptors on any post-synaptic cell. Unlike a computer, brain cells don’t need to use electrical signals to transmit important information; cellular signaling often happens through vastly complicated networks of cascading chemical reactions. In this way, axo-myelinic synapses are a completely untapped therapeutic target that are likely involved in all myelin-related diseases. But practically nothing is known about the function of these newly discovered synapses. Despite the lack of hard evidence, we can make some educated speculations about the role of axo-myelinic communication in our brains. (I won’t dig too deeply into the details here, so if you want more information about the possible molecular mechanisms you can check out my qualifying exam and its associated figures).

There are three probable ways in which axo-myelinic synapse activity could affect neurons and oligodendrocytes. We’ve already briefly touched on the first: the activity-dependent delivery of vital nutrients. As we discussed, myelin prevents axons from taking in vital nutrients, so oligodendrocytes deliver the food directly to the neuron. It seems extraordinarily likely that the amount of energy delivered to a given neuron would depend on the activity level of specific axons. And this information would be easily communicated through axo-myelinic synapses (see the top portion of the figure below). Secondly, axo-myelinic synapses are an attractive mechanism to explain how oligodendrocytes determine the thickness of their myelin wrappings. By using axo-myelinic synapses as a read-out of neuronal activity, an oligodendrocyte could fine tune the structure of each individual myelin sheath to modulate the speed of neuronal signaling (see the bottom portion of the figure below).

This is a figure I created to visualize the hypothetical ways in which axo-myelinic synapses might function. Top part of the figure: PKC is immediately activated by low frequency action potential firing which perfuses lactate into myelin through monocarboxylate transporter 1 (MCT) where it is delivered to actively firing axons through MCT2. Bottom part of the figure: High frequency action potentials cause a delayed inhibition of MAPK through myelinic NMDA receptor activation which enhances mRNA translation in myelin.

Finally, the interplay of these two mechanisms raises other fascinating possibilities. Because oligodendrocytes myelinate up to 60 different axons, they are in a perfect position to control the activity of an entire neuronal network. By receiving information from hundreds of axo-myelinic synapses, an oligodendrocyte could selectively provide nutrients to certain axons while also changing the structure of individual myelin sheaths. The combination of these abilities provides oligodendrocytes with an immense power to orchestrate the information processing of a group of neurons. An oligodendrocyte could starve out specific neurons by withholding nutrients, or it could alter the myelination on particular axons to synchronize activity across a network. We don’t really know if any of this happens, but the mere possibilities are mind-boggling. Whatever the actual functions of axo-myelinic synapses turn out to be, oligodendrocytes clearly play a much more important role in the brain than they receive credit for.