Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment

Traumatic axonal injury (TAI) is a consistent component of traumatic brain injury (TBI), and is associated with much of its morbidity. Increasingly, it has also been recognized as a major pathology of mild TBI (mTBI). In terms of its pathogenesis, numerous studies have investigated the susceptibility of the nodes of Ranvier, the paranode and internodal regions to TAI. The nodes of Ranvier, with their unique composition and concentration of ion channels, have been suggested as the primary site of injury, initiating a cascade of abnormalities in the related paranodal and internodal domains that lead to local axonal swellings and detachment. No investigation, however, has determined the effect of TAI upon the axon initial segment (AIS), a segment critical to regulating polarity and excitability. The current study sought to identify the susceptibility of these different axon domains to TAI within the neocortex, where each axonal domain could be simultaneously assessed. Utilizing a mouse model of mTBI, a temporal and spatial heterogeneity of axonal injury was found within the neocortical gray matter. Although axonal swellings were found in all domains along myelinated neocortical axons, the majority of TAI occurred within the AIS, which progressed without overt structural disruption of the AIS itself. The finding of primary AIS involvement has important implications regarding neuronal polarity and the fate of axotomized processes, while also raising therapeutic implications, as the mechanisms underlying such axonal injury in the AIS may be distinct from those described for nodal/paranodal injury.