In a groundbreaking study, researchers question a long-standing belief in neuroscience regarding the structure of axons, which are the slender, elongated fibers that extend from nerve cells and convey electrical signals between them. They introduce a novel perspective on how information flows within the brain. The research, spearheaded by Shigeki Watanabe from Johns Hopkins School of Medicine, collaborated partially with the Marine Biological Laboratory (MBL) Neurobiology course and has been published in Nature Neuroscience.
For over 70 years, axons have been illustrated as exceedingly thin wires, changing in diameter along their length but generally resembling a cylindrical shape. It was commonly believed that electrical signals (action potentials) traverse these axons at a steady speed, akin to vehicles moving swiftly through a tunnel. This understanding dates back to the pioneering work of Alan Hodgkin and Andrew Huxley in the 1940s and 50s, which largely took place at MBL.
Contrary to this traditional view, Watanabe and his team illustrate that axons actually exhibit a “pearls-on-a-string” structure at the nanoscale. This means there are lengths of cable interspersed with protrusions they refer to as “nano-pearls” or nonsynaptic boutons. They propose that the speed at which action potentials travel is not fixed but varies due to the size fluctuations of these nano-pearls, which result from mechanical alterations in the axon’s membrane and cytoskeleton during signal transmission.
“Imagine this as cars navigating a highway,” explains Watanabe. “On a four-lane highway that abruptly narrows to one lane and then expands back to four, you’d expect traffic flow to be impacted. That’s a more accurate representation of how axons operate.”
“Interestingly, the dimensions of these pearls-on-a-string can change at specific sites,” Watanabe adds. “Our findings indicate we can influence the size of nano-pearls by altering local conditions, like cholesterol levels in the plasma membrane, which in turn affects the speed of action potentials. This suggests that axons possess significant flexibility.”
Discovery Through Flash-Freezing Techniques
The unique axon structure described by Watanabe’s team lies beyond the limits of light microscopy, with axon diameters near 60 nm and nano-pearls measuring around 200 nm. These observations were made in unmyelinated axons from mouse nervous systems.
“The reason previous studies overlooked this axon structure is due to traditional examining methods. We used cryo-preserved samples under an electron microscope,” noted Watanabe. “Typically, researchers employ chemical processes for electron microscopy, dehydrating the samples—much like turning a grape into a raisin. Conversely, cryo-preservation maintains the actual shape by freezing the tissue, akin to preserving a grape’s fresh form.”
Insights into Neurodegenerative Diseases
This discovery has significant implications for understanding neurodegenerative diseases, according to Watanabe. For instance, Alzheimer’s disease is linked with cholesterol dysregulation within the brain. The study highlights how changes in cholesterol levels can alter the size of nano-pearls, subsequently affecting action potential conduction speeds. Impairments in this mechanism may contribute to axonal damage and cell death.
“It will be fascinating to explore how mutations related to neurodegeneration influence axon structure and whether plasticity remains in those neurons,” he remarked.
Since 2015, Watanabe has been involved with the MBL Neurobiology course, where part of the research took place. The lead author, Jacqueline Griswold, alongside co-authors Siyi Ma and Renee Pepper, are all alumni of the MBL Neurobiology course.
This research was supported in part by a Whitman Fellowship awarded to Watanabe at MBL.
