Role of p75NTR in NMDAR-mediated excitotoxic brain injury in neonatal mice

Background: Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75NTR) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75NTR can, in addition to its trophic function, also induce apoptosis. Hypothesis: We hypothesised that excitotoxicity increases p75NTR expression and p75NTR knockout (KO) mice have a significantly smaller lesion size upon excitotoxicity as compared to wild-type (WT) mice. Methods: We used an established animal model of neonatal excitotoxic brain injury mimicking several key aspects of human preterm brain damage. We subjected five-day-old WT and KO mice to excitotoxic injury by means of a single intracranial ibotenate injection (N-methyl-D-aspartate receptor agonist, NMDAR) into one brain hemisphere. Lesion size, number of activated caspase-3- and apoptosis-inducing factor (AIF)-positive cells were determined as outcome parameters. Gender analyses were taken into account retrospectively. Results: NMDAR-mediated excitotoxicity induced an upregulation of p75NTR expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75NTR reduced the number of activated caspase-3 but not AIF-positive cells after NMDAR-mediated excitotoxic injury independently of gender. Conclusion: Since NMDAR-mediated excitotoxic brain injury induced p75NTR expression and caspase-3-activated apoptosis in p75NTR KO animals was decreased, we conclude that activation of p75NTR contributes to NMDAR-mediated apoptosis in the neonatal brain. An increase in lesion size in female animals after excitotoxic brain injury suggests that in females p75NTR seems to play a dual role.

Research Highlights
► In the neonatal rodent brain NMDAR-mediated excitotoxic brain injury is associated with an increased expression of the p75NTR.
► Knockout of p75NTR reduces caspase-3 activated apoptosis and lesion size due to NMDAR activation.
► For p75NTR activation gender seems to play a dual role.