Rapid Repeat Exposure to Subthreshold Trauma Causes Synergistic Axonal Damage and Functional Deficits in the Visual Pathway in a Mouse Model

We examined the effect of repeat exposure to a non-damaging insult on central nervous system axons using the optic projection as a model. The optic projection is attractive because its axons are spatially separated from the cell bodies, it is easily accessible, it is composed of long axons, and its function can be measured. We performed closed-system ocular neurotrauma in C57Bl/6 mice using bursts of 15 or 26-psi (pounds per square inch) overpressure air that caused no gross damage. We quantified the visual evoked potential (VEP) and total and degenerative axons in the optic nerve. Repeat exposure to a 15-psi air blast caused more axon damage and vision loss than a single exposure to a 26-psi air blast. However, an increased VEP latency was detected in both groups. Exposure to three 15-psi air blasts separated by 0.5 sec caused 15% axon degeneration at 2 weeks. In contrast, no axon degeneration above sham levels was detected when the interinjury interval was increased to 10 min. Exposure to 15-psi air blasts once a day for 6 consecutive days caused 3% axon degeneration. Therefore, repeat mild trauma within an interinjury interval of 1 min or less causes synergistic axon damage, whereas mild trauma repeated at a longer interinjury interval causes additive, cumulative damage. The synergistic damage may underlie the high incidence of traumatic brain injury and traumatic optic neuropathy in blast-injured service members given that explosive blasts are multiple injury events that occur in a very short time span. This study also supports the use of the VEP as a biomarker for traumatic optic neuropathy.