Membrane mechanics dictate axonal pearls-on-a-string morphology and function, 2024, Griswold et al.

[SNT Gatchaman]

Membrane mechanics dictate axonal pearls-on-a-string morphology and function
Griswold, Jacqueline M.; Bonilla-Quintana, Mayte; Pepper, Renee; Lee, Christopher T.; Raychaudhuri, Sumana; Ma, Siyi; Gan, Quan; Syed, Sarah; Zhu, Cuncheng; Bell, Miriam; Suga, Mitsuo; Yamaguchi, Yuuki; Chéreau, Ronan; Valentin Nägerl, U.; Knott, Graham; Rangamani, Padmini; Watanabe, Shigeki

Axons are ultrathin membrane cables that are specialized for the conduction of action potentials. Although their diameter is variable along their length, how their morphology is determined is unclear.

Here, we demonstrate that unmyelinated axons of the mouse central nervous system have nonsynaptic, nanoscopic varicosities ~200 nm in diameter repeatedly along their length interspersed with a thin cable ~60 nm in diameter like pearls-on-a-string. In silico modeling suggests that this axon nanopearling can be explained by membrane mechanical properties.

Treatments disrupting membrane properties, such as hyper-or hypotonic solutions, cholesterol removal and nonmuscle myosin II inhibition, alter axon nanopearling, confirming the role of membrane mechanics in determining axon morphology. Furthermore, neuronal activity modulates plasma membrane cholesterol concentration, leading to changes in axon nanopearls and causing slowing of action potential conduction velocity.

These data reveal that biophysical forces dictate axon morphology and function, and modulation of membrane mechanics likely underlies unmyelinated axonal plasticity.

Link | PDF (Nature Neuroscience) [Open Access]

 

[SNT Gatchaman]

In the mammalian central nervous system, high-frequency electrical stimulation (HFS) induces nanoscale remodeling of axonal morphology, where a transient enlargement of synaptic varicosities (by 20%) is followed by a sustained widening of the axons (by 5%). This, in turn, leads to bidirectional changes in AP conduction velocity, as predicted by the cable theory considering the biophysical effects of membrane capacitance and axial resistance. Thus, seemingly minute changes in axon morphology can sensitively tune AP conduction and overall neuronal function.

Beyond the membrane, the contribution of the cytoskeleton to axon morphology has become more appreciated after the discovery of the membrane periodic cytoskeleton (MPS). Unlike other cellular compartments, axons have a unique cytoskeletal structure, in addition to more traditional cortical actin.

Recently, the structure of the cytoskeleton in mature axons has been extensively studied to reveal that, unlike other cells, axons have a unique and periodic actomyosin cytoskeleton, the MPS. The motor protein NMII, which binds within one actin ring, serves to dilate the MPS during organelle trafficking and electrical activity.

Our study uncovers further morphological complexity in that unmyelinated axons in the mammalian central nervous system under near-physiological conditions have a pearls-on-a-string morphology due to membrane-driven instability.

We validated our modeling by showing that treatments that affect membrane mechanics, such as fluctuations in extracellular osmotic pressure, membrane cholesterol concentration manipulation or cytoskeletal manipulation, cause predictable changes in pearling behavior. […] We further demonstrate that axon pearl dimensions increase with HFS and that this plasticity changes AP velocity. This structural plasticity is accompanied by a 45% decrease in membrane cholesterol, suggesting a mechanism by which the pearl shape could be altered. Indeed, AP conduction velocity fails to change after artificial cholesterol removal, although some structural plasticity remains.

Axon pearling is a well-characterized phenomenon that occurs even at the macroscopic level in neurons under stress. However, the morphology described here is on a nanoscale, with an axon tract ~60 nm in diameter and repeated varicosities ~200 nm in diameter. The difference between the two regions is far below the diffraction limit of light, making ultrastructural characterization essential.

Axon nanopearling has strong implications for AP propagation in unmyelinated axons. Previous work with cable theory modeling predicts that sudden changes in axon diameter would slow AP propagation and at a certain size cause AP propagation to fail. In agreement with this theory, our results also suggest that AP conduction velocity is strongly dependent on axon geometry. In particular, connector diameter has a linear relationship with velocity, as the cable theory predicts. However, the relationship between AP velocity and axon morphology is more complicated because of nanopearling. Simultaneous changes between two axon dimensions reveal an optimal NSV length-to-width ratio (~1.7), where AP velocity is at its peak. Higher and lower than this value would result in slower AP conduction velocity.

One very intriguing idea that arises from our study is that direct modulation of biophysical forces and axon morphology could tune AP propagation velocity. AP propagation tuning occurs in myelinated neurons where myelination placement and length are tightly regulated, creating specific firing patterns important for various circuit functions such as coincident detection. Through our modeling, we can probe the effect of changing axon nanopearling on AP propagation tuning in unmyelinated axons. In treatments that cause a dramatic change in nanopearling, our modeling predicts a shift in AP propagation velocity.

Finally, changes in membrane lipids have also been linked to changes in AP propagation.

Our results suggest that cholesterol depletion by MβCD slows down AP propagation velocity. This effect may be due to the direct modulation of axon nanopearling. However, cholesterol also plays an important role in channel clustering, and, thus, axon morphology may not be the sole contributor. Nonetheless, our work suggests a neuronal plasticity paradigm whereby modulation of biophysical factors controls axon nanopearling and thus AP conduction velocity.

 

[SNT Gatchaman]

high-frequency electrical stimulation (HFS) induces nanoscale remodeling of axonal morphology

Relevance to ECT? Edit: or perhaps more likely deep-brain neuro-stimulation in Parkinson's and others.

AP propagation tuning occurs in myelinated neurons where myelination placement and length are tightly regulated, creating specific firing patterns important for various circuit functions such as coincident detection. […] In treatments that cause a dramatic change in nanopearling, our modeling predicts a shift in AP propagation velocity.

FND?