Traumatic brain injuryinduced axonal phenotypes r

Authors: Anders Hånell John E Greer Melissa J McGinn John T Povlishock

Publish Date: 2014/12/21

Volume: 129, Issue: 2, Pages: 317-332

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Abstract

Injured axons with distinct morphologies have been found following mild traumatic brain injury mTBI although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology This complicates evaluation of therapeutic interventions targeting axonal injury To address this issue we assessed axonal injury over time within a welldefined axonal population while also evaluating mitochondrial permeability transition as a therapeutic target We utilized mice expressing yellow fluorescent protein YFP in cortical neurons which were crossed with mice which lacked Cyclophilin D CypD a positive regulator of mitochondrial permeability transition pore opening Their offspring were subjected to mTBI and the ensuing axonal injury was assessed using YFP expression and amyloid precursor protein APP immunohistochemistry visualized by confocal and electron microscopy YFP+ axons initially developed a single APP+ focal swelling proximal bulb which progressed to axotomy Disconnected axonal segments developed either a single bulb distal bulb or multiple bulbs varicosities which were APP− and whose ultrastructure was consistent with ongoing Wallerian degeneration CypD knockout failed to reduce proximal bulb formation but decreased the number of distal bulbs and varicosities as well as a population of small APP+ callosal bulbs not associated with YFP+ axons The observation that YFP+ axons contain several pathological morphologies points to the complexity of traumatic axonal injury The fact that CypD knockout reduced some but not all subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategiesThe authors thank Carol Davis Susan Walker and Jesse Sims for invaluable technical assistance Scott Henderson and Frances White for sharing their expertise in confocal microscopy Audrey Lafrenaye Vishal Patel and Michal Vascak for scientific discussions and comments on this manuscript as well as Michael Forte and Paolo Bernardi for generating and providing the CypD KO mice This work was funded by NIH grants NS077675 and NS047463

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