title: Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury.
abstract: Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.|Department of Ophthalmology, University of South Florida, Tampa, FL, United States of America.|James A. Haley Veteran's Administration, Tampa, FL, United States of America.
authors.forename: Radouil
authors.initials: R
authors.lastname: Tzekov
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.
authors.forename: Clint
authors.initials: C
authors.lastname: Dawson
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.
authors.forename: Megan
authors.initials: M
authors.lastname: Orlando
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.|James A. Haley Veteran's Administration, Tampa, FL, United States of America.
authors.forename: Benoit
authors.initials: B
authors.lastname: Mouzon
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.|James A. Haley Veteran's Administration, Tampa, FL, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Evans
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.
authors.forename: Gogce
authors.initials: G
authors.lastname: Crynen
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
authors.affiliation: The Roskamp Institute, Sarasota, FL, United States of America.|James A. Haley Veteran's Administration, Tampa, FL, United States of America.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001930:Brain Injuries / Q000150:complications* / Q000503:physiopathology; D002908:Chronic Disease; D006801:Humans; D008055:Lipids / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D020543:Proteome / Q000032:analysis; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D014786:Vision Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology*
chemical_list: D015415:Biomarkers; D008055:Lipids; D020543:Proteome