Abstract
Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM) to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy. Our proposed computational model accurately simulates the median value of the Young’s modulus of the axon plasma membrane determined by atomic force microscopy. It also predicts that because the spectrin filaments are under entropic tension, the thermal random motion of the voltage-gated sodium channels (Nav), which are bound to ankyrin particles, a critical axonal protein, is reduced compared to the thermal motion when spectrin filaments are held at equilibrium. Lastly, our model predicts that because spectrin filaments are under tension, any axonal injuries that lacerate spectrin filaments will likely lead to a permanent disruption of the membrane skeleton due to the inability of spectrin filaments to spontaneously form their initial under-tension configuration.
Highlights
It is known for some time that microtubules and neurofilaments are the predominant structural filamentous proteins in the axon [1, 2]
In the case of the axon, we considered the following experimental findings: (i) The spatial distribution of ankyrin-G is highly periodic in the proximal area of the axon, while ankyrin-B exhibits a periodic pattern in distal axons [3, 5], (ii) Nav channels exhibit a periodic distribution pattern in the axon initial segment (AIS) alternating with actin rings [3], (iii)
Imaginary cylinder (Fig 3A), ri is the distance between particle i and the center-line of the axon, rS is the radius of the spectrin particle and rA is the radius of the actin particle
Summary
Super-resolution microscopy has suggested that the actin cytoskeleton structure differ between various neuronal subcompartments. To determine the possible implication of the differing actin cytoskeleton structure, we determined the stiffness of the plasma membrane of neuronal subcompartments using atomic force microscopy (AFM). By using a particle-based model for the surface membrane skeleton of the axon that comprises actin rings connected with spring filaments to represent the axonal structure, we show that regions neighboring actin rings are stiffer than areas between these rings. In these in between sub-regions, the spectrin filaments determine stiffness. Our modeling shows that because the spectrin filaments are under tension, the thermal jitter of the actin-associated ankyrin particles, connected to the middle area of spectrin filaments, is minimal. We predict that laceration of the spectrin filaments due to injury will cause a permanent damage to the axon since spontaneous repair of the spectrin network is not possible as spectrin filaments are under entropic tension
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