title: Traumatic brain injury-induced axonal phenotypes react differently to treatment.
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 well-defined 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 knock-out 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 knock-out reduced some, but not all, subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategies.
authors.affiliation: Department of Anatomy and Neurobiology, Medical College of Virginia Campus of Virginia Commonwealth University, Post Office Box 980709, Richmond, VA, 23298-0709, USA.
authors.forename: Anders
authors.initials: A
authors.lastname: Hånell
authors.forename: John E
authors.initials: JE
authors.lastname: Greer
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: McGinn
authors.forename: John T
authors.initials: JT
authors.lastname: Povlishock
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology*; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D014855:Wallerian Degeneration / Q000378:metabolism / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D001426:Bacterial Proteins; D000081406:Peptidyl-Prolyl Isomerase F; D008164:Luminescent Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; C054562:yellow fluorescent protein, Bacteria; D021983:Cyclophilins