Delayed neuromotor recovery and increased memory acquisition dysfunction following experimental brain trauma in mice lacking the DNA repair gene XPA: Laboratory investigation

摘要

Object. This study investigates the outcome after traumatic brain injury (TBI) in mice lacking the essential DNA repair gene xeroderma pigmentosum group A (XPA). As damage to DNA has been implicated in neuronal cell death in various models, the authors sought to elucidate whether the absence of an essential DNA repair factor would affect the outcome of TBI in an experimental setting. Methods. Thirty-seven adult mice of either wild-type (n = 18) or XPA-deficient ("knock-out" [n = 19]) genotype were subjected to controlled cortical impact experimental brain trauma, which produced a focal brain injury. Shaminjured mice of both genotypes were used as controls (9 in each group). The mice were subjected to neurobehavoral tests evaluating learning/acquisition (Morris water maze) and motor dysfunction (Rotarod and composite neuroscore test), pre- and postinjury up to 4 weeks. The mice were killed after 1 or 4 weeks, and cortical lesion volume, as well as hippocampal and thalamic cell loss, was evaluated. Hippocampal staining with doublecortin antibody was used to evaluate neurogenesis after the insult. Results. Brain-injured XPA -/- mice exhibited delayed recovery from impairment in neurological motor function, as well as pronounced cognitive dysfunction in a spatial learning task (Morris water maze), compared with injured XPA +/+ mice (p 0.05). No differences in cortical lesion volume, hippocampal damage, or thalamic cell loss were detected between XPA +/+ and XPA -/- mice after brain injury. Also, no difference in the number of cells stained with doublecortin in the hippocampus was detected. Conclusions. The authors' results suggest that lack of the DNA repair factor XPA may delay neurobehavioral recovery after TBI, although they do not support the notion that this DNA repair deficiency results in increased cell or tissue death in the posttraumatic brain.