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.
Highlights
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, including in the US, where annual incidence is approximately 1.7 million [1]
Despite the fact that no fixative was used for perfusion at the time of anesthesia, there was only minimal retinal loss and the retinas were well-preserved for image analysis
Examination of retinal flatmounts demonstrated a relative reduction in the total number of the brain-specific homeobox/POU domain protein 3A (Brn-3a)-positive retinal ganglion cells in mice subjected to TBI in the inner retinal locations from 228.1 ± 31 cells/field for r-sham to 181.4 ± 71.4 for Repetitive mild traumatic brain injury (r-mild TBI (mTBI))—a 20.5% decrease (p = 0.019, t-test)
Summary
Traumatic brain injury (TBI) is a major cause of death and disability worldwide, including in the US, where annual incidence is approximately 1.7 million [1]. TBI severity is commonly described as mild, moderate, or severe based on a number of factors, but concussion, or mild TBI (mTBI), is the most common form of TBI, accounting for up to 75% of all brain injuries occurring annually in the US [1]. Extensive neurobehavioral and neuropathological analyses of this model have demonstrated the deleterious effects of r-mTBI on brain morphology and cognitive function. We described negative consequences for the visual system at 10 to 13 weeks post injury, such as decreased optic nerve diameters, increased cellularity and areas of demyelination in optic nerves in r-mTBI versus control (repeated sham, or r-sham) mice [10]. Thinning of the inner retina and an effect on the visual function manifested by a decrease in the amplitude of the photopic negative response of the electroretinogram were observed
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