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.

轴突是专门用于传导动作电位的超薄膜电缆。尽管它们的直径沿其长度变化，但尚不清楚它们的形态是如何确定的。在这里，我们证明小鼠中枢神经系统的无髓轴突具有非突触的纳米级静脉曲张，沿其长度反复出现直径 ~200 nm 的细电缆，就像绳子上的珍珠一样。计算机模拟表明，这种轴突纳米珍珠化可以用膜的机械特性来解释。破坏膜特性的治疗，例如高渗或低渗溶液、胆固醇去除和非肌肉肌球蛋白 II 抑制，改变了轴突纳米珍珠化，证实了膜力学在确定轴突形态中的作用。此外，神经元活动调节质膜胆固醇浓度，导致轴突纳米珍珠发生变化并导致动作电位传导速度减慢。这些数据表明，生物物理力决定了轴突的形态和功能，而膜力学的调节可能是无髓轴突可塑性的基础。