A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse.

Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON. Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions. Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare. Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.

Multifocal Electroretinography in the Presence of Temporal and Spatial Correlations and Eye Movements.

Releasing patients from the fixation task, and permitting them to view natural stimuli such as movies, would provide increased comfort, and potentially additional signs of retinal function, when recording multifocal electroretinograms (mfERGs). Techniques must be developed to handle the difficulties that arise from these alternative stimulation strategies. Multifocal stimuli were presented to volunteer human subjects with and without fixation. Retinocentric analyses were performed to deal with shifts of the stimulus across the retina in the presence of eye movements. Artificial scotomas that moved with the eyes to simulate local retinal defects were presented to assess whether such defects might be detectable in the presence of eye movements. Temporal and spatial correlations in the stimulus can be discounted, permitting retinal kernels to be measured in response to natural stimuli. Responses to temporally natural stimuli tend to have slightly stronger amplitudes because of the presence of low temporal frequencies in these stimuli. The effects of eye movement artifacts can be reduced, permitting similar kernels to be obtained in the absence and presence of eye movements. Convergence to stable kernels took slightly longer in the presence of temporal correlations or eye movements. Artificial scotomas can be localized with these methods. It may be possible to perform multifocal ERG recordings in the clinic using more flexible, natural techniques. However, work is needed to achieve results comparable to those routinely obtained with conventional methods.

Arginase 2 deletion reduces neuro-glial injury and improves retinal function in a model of retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP. METHODS AND FINDINGS: Studies were performed using wild type (WT) and A2 knockout (A2-/-) mice exposed to Oxygen Induced Retinopathy (OIR). Neuronal injury and apoptosis were assessed using immunohistochemistry, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end) labeling and Western blotting. Electroretinography (ERG) was used to assess retinal function. Neuro-glial injury in WT ROP mice was evident by TUNEL labeling, retinal thinning, decreases in number of rod bipolar cells and glial cell activation as compared with room air controls. Significant reduction in numbers of TUNEL positive cells, inhibition of retinal thinning, preservation of the rod bipolar cells and prevention of glial activation were observed in the A2-/- retinas. Retinal function was markedly impaired in the WT OIR mice as shown by decreases in amplitude of the b-wave of the ERG. This defect was significantly reduced in A2-/- mice. Levels of the pro-apoptotic proteins p53, cleaved caspase 9, cytochrome C and the mitochondrial protein Bim were markedly increased in WT OIR retinas compared to controls, whereas the pro-survival Mitochondrial protein BCL-xl was reduced. These alterations were largely blocked in the A2-/- OIR retina. CONCLUSIONS: Our data implicate A2 in neurodegeneration during ROP. Deletion of A2 significantly improves neuronal survival and function, possibly through the regulation of mitochondrial membrane permeability mediated apoptosis during retinal ischemia. These molecular events are associated with decreased activation of glial cells, suggesting a rescue effect on macroglia as well.