The axonal actin-spectrin lattice acts as shock absorbers to protect neurons from stretch-induced damage

Abstract

Axons are thin tubular extensions generated by neuronal cells to transmit signals across long distances. In the peripheral and the central nervous systems, axons experience large deformations during normal activity or as a result of injury. Yet, axon biomechanics, and its relation to the internal structure that allows axons to withstand such deformations, is poorly understood. Up to now, it has been generally assumed that microtubules and their associated proteins are the major load-bearing elements in axons. We revise this view point by combining mechanical measurements using a custom developed force apparatus with biochemical or genetic modifications to the axonal cytoskeleton, revealing an unexpected role played by the actin-spectrin skeleton. For this, we first demonstrate that axons exhibit a reversible strain-softening response, where its steady state elastic modulus decreases with increasing strain. We then explore the contributions from the various cytoskeletal components of the axon, and show that the recently discovered membrane-associated skeleton consisting of periodically spaced actin filaments interconnected by spectrin tetramers play a prominent mechanical role. Finally, using a theoretical model we argue that the actin-spectrin skeleton act as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to buffer excess mechanical stress.