The role of mechanics in axonal stability and development

Neuronal cells have evolved to span long distances within an organism by extending thin tubular protrusions called axons and dendrites. Of these axons are of particular interest as they often reach extreme lengths, of the order of a meter in a human and tens of meters in a blue whale. Such spatial scales pose several challenges to the neuronal cells, which include the need to transport materials over long distances, regulation of growth and retraction dynamics, and maintenance of structural integrity.

It is becoming increasingly clear that mechanical forces are critical in neuronal development, stability and function (recently reviewed in [1], [2], [3]). For example, it has been shown that mechanical tension regulates axonal initiation [4], [5], growth [4], [6], and synaptogenesis [7]. It has also been proposed that mechanical tension generated by axons may play an important role in the formation of cortical folds in primates [8], [9].

Perturbations to mechanical balance between the cytoskeletal elements cause axonal retraction and this involves actin and microtubule-associated molecular motors, polymerization dynamics, and passive cytoskeletal mechanics [10], [11], [12]. Such perturbations to axons in vitro cause morphological changes like axonal beading or spheroids like those seen in pathological conditions, and loss of mechanical balance is implicated in this as well [13], [14]. Thus understanding the roles of active and passive forces in axons is expected to be relevant in understanding axonal degeneration as well as rewiring.

Even under normal functioning, axons need to withstand large stretch deformations in animals during movement [15], [16]. In extreme cases, it can be as large as 160% as in the case of some baleen whales and hence may have evolved various mechanical strategies for neuroprotection [17]. Extreme stretch leads to axonal damage, which includes stretch injury to nerves, concussion, and traumatic brain injury. Nerve compression resulting from injury or ageing-related conditions also highlights the role of axonal mechanics in debilitating conditions.

In this review, we discuss our current understanding of axonal mechanics in a few select contexts. We restrict ourselves to the cytoskeletal and membrane of the axonal shaft and how their mechanics influences axonal stability. We begin this review by describing some of the salient or unique features of the axonal cytoskeleton. We then give a summary of some of the technical developments in the field that has enabled us to probe axonal mechanical responses of this composite cytoskeleton. The cytoskeletal responses to stretch are divided into short timescale passive and active behaviors followed by long-timescale growth effects mainly for ease of discussion. As the axon is highly anisotropic, radial compression response is discussed separately along with mechanical aspects of calibre maintenance and shape instabilities arising out of cytoskeletal perturbations. Finally, we discuss the often ignored mechanical aspects of the axonal membrane, and its relevance to the setting of optimal calibre and abnormal shape transformations. Throughout this review, we have tried to bring out the complex responses of the axonal ultrastructure focussing our attention mainly on experiments.

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