Myelin Sheath Decompaction, Axon Swelling, and Functional Loss during Chronic Secondary Degeneration in Rat Optic Nerve

PURPOSE. To examine chronic changes occurring at 6 months following partial optic nerve (ON) transection, assessing optic axons, myelin, and visual function. METHODS. Dorsal ON axons were transected, leaving ventral optic axons vulnerable to secondary degeneration. At 3 and 6 months following partial transection, toluidine-blue stained sections were used to assess dimensions of the ON injury site. Transmission electron microscopy (TEM) images of ventral ON were used to quantify numbers, diameter, area, and myelin thickness of optic axons. Immunohistochemistry and fluoromyelin staining were used to assess semiquantitatively myelin protein, lipids in ventral ON, and retinal ganglion cells (RGCs) in midventral retina. Visuomotor function was assessed using optokinetic nystagmus. RESULTS. Following partial ON transection, optic axons and function remained disrupted at 6 months. Although ventral ON swelling observed at 3 months (P <= 0.05) receded to normal by 6 months, ultrastructurally, myelinated axons remained swollen (P >= 0.05), and myelin thickness increased (P <= 0.05) due to loosening of lamellae and an increase in the number of intraperiodic lines. Axons with decompacted myelin persisted and were distinguished as having large axonal calibers and thicker myelin sheaths. Nevertheless, progressive loss of myelin lipid staining with fluoromyelin was seen at 6 months. Despite no further loss of ventral optic axons between 3 and 6 months (P >= 0.05), visuomotor function progressively declined at 6 months following partial transection (P <= 0.05). CONCLUSIONS. Continued decompaction of myelin, altered myelin structure, and swelling of myelinated axons are persistent features of the chronic phases of secondary degeneration and likely contribute to progressive loss of visual function. (Invest Ophthalmol Vis Sci. 2012; 53: 6093-6101) DOI: 10.1167/iovs.12-10080