Chronic Swelling and Abnormal Myelination during Secondary Degeneration after Partial Injury to a Central Nervous System Tract

Abstract

Secondary degeneration is a serious consequence of traumatic injury to the central nervous system (CNS) and involves the progressive loss of neurons and function. However, while disruption to myelin has been observed in spared axons, the ultrastructural abnormalities that occur in myelin and axons spatially separated from the primary injury and susceptible exclusively to secondary degeneration are unknown. We used a model of secondary degeneration in which the dorsal aspect of rat optic nerve (ON) was transected leaving the central/ventral ON undamaged, but vulnerable to secondary degeneration. Transmission electron microscopy of the central/ventral ON at 1 and 3 months was used to quantify secondary changes in axon diameter, myelin sheath thickness and morphology, compared to normal animals. Three months after partial ON transection, cross-sectional nerve area at the injury site was increased (p ≤ 0.05), and changes in axons and myelin sheaths were detected in the central/ventral ON. Although myelin sheath thickness remained normal at both time points, average axon diameter significantly increased at 3 months. The density of the total axon population was decreased by 1 month, reflecting loss of retinal ganglion cells as previously published, with a decrease in the density of normally-myelinated axons, but an increase in unmyelinated axon density (p ≤ 0.05). Myelin basic protein immunoreactivity and fluoromyelin staining were also significantly reduced. Within four subpopulations of abnormally-myelinated axons, there was: no change in lightly-myelinated axons; an increase in axons with excessive myelination (at 1 month); and an increase in the density of axons with partial and fully-decompacted myelin (at 3 months, p ≤ 0.05). Chronic axon swelling and myelin sheath compaction defects are features of secondary degeneration, and may contribute to the reported loss of ON function following partial transection.