Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain.

Traumatic brain injury (s) is a leading cause of disability among young children and is associated with long-term cognitive deficits. These clinical findings have prompted an investigation of the hippocampus in an experimental model of trauma to the developing brain at postnatal day (p21). Previous studies using this model have revealed a progressive loss of neurons in the hippocampus as brain-injured animals mature to young adulthood. Here we determine if this hippocampal vulnerability is likewise reflected in altered neurogenesis and if the antioxidant glutathione peroxidase (GPx) modulates neurogenesis during maturation of the injured, immature brain. Male transgenic mice that overexpress glutathione peroxidase (GPx) and wildtype littermates were subjected to controlled cortical impact or sham surgery on p21. At two weeks postinjury, the numbers of proliferating cells and immature neurons within the subgranular zone were measured using Ki-67 and doublecortin, respectively. Bromodeoxyuridine (BrdU) was used to label dividing cells beginning two weeks postinjury. Survival (BrdU+) and neuronal differentiation (BrdU+/ NeuN+) were then measured four weeks later with confocal microscopy. Two-way ANOVA revealed no significant interaction between genotype and injury. Subsequent analysis of the individual effects of injury and genotype, however, showed a significant reduction in subgranular zone proliferation (Ki-67) at two weeks postinjury (p=0.0003) and precursor cell survival (BrdU+) at six weeks postinjury (p=0.016) and a trend towards reduced neuronal differentiation (BrdU+/ NeuN+) at six weeks postinjury (p=0.087). Overall, these data demonstrate that traumatic injury to the injured immature brain impairs neurogenesis during maturation and suggest that GPx cannot rescue this reduced neurogenesis.