AXONAL RESPONSE TO INJURY

 

The optic nerve is regarded as an extension of the brain. It is usually recognized that once damaged, the optic nerve does not regenerate, leading to visual loss lasting the lifetime of the individual. The degeneration of the optic nerve follows a timeline of events, starting milliseconds to hours after the initiating event, such as trauma or ischemia.

One of the earliest effects is the entry of calcium ions (Ca⁺⁺) into the site, through voltage-gated calcium channels, as well as, possibly from the endoplasmic reticulum. This increased Ca⁺⁺ activates calpains, which are commonly occurring cysteine proteases, mechanistically linking injury-induced calcium signaling to subsequent axonal degeneration by the process of cytoskeletal degradation. Following this, the axons swell and fragment on both sides of the injury. In murine spinal cord, the same fragmentation process can be completely blocked by calpain inhibitors.

A few days later, the distal axon segments fragment through a process called Wallerian degeneration in which the cytoskeleton is degenerated. The axon first forms swellings and then fragments into self-enclosed units, and the myelin disintegrates into elliptical structures. The proximal axonal segment forms a retraction bulb, elliptical in shape and several times the axonal diameter. This bulb grows progressively larger over weeks as the axonal cytoskeleton depolymerizes and the axon dies back towards the soma.  

The first week following the event is critical as the inflammatory response reaches its peak. Infiltrating monocyte-derived macrophages arrive at the optic nerve after the first day.

Astrocytes at the injury site in the optic nerve degenerate within 3 days and begin to repopulate by day 7. Optic nerve head astrocytes become reactive, losing many fine processes and shrinking in total area covered, but thickening both their soma and primary processes. Retinal microglia increase in number, presumably through proliferation.

The retinal ganglion cell soma receives the signal that it has been damaged within the first week, and many stress responses are subsequently activated. Whether the RGC will die or regenerate is determined in that first week after injury, and this fate depends on various intrinsic and extrinsic factors.

REFERENCE:

Fague L, Liu YA, Marsh-Armstrong N. The basic science of optic nerve regeneration. Ann Transl Med. 2021 Aug;9(15):1276. doi: 10.21037/atm-20-5351. PMID: 34532413; PMCID: PMC8421956.