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

Brain Res. 2010 Oct 8;1355:31-40. doi: 10.1016/j.brainres.2010.07.095. Epub 2010 Aug 6.


Background: Perinatal brain injury in preterm infants is a major cause of neurological handicap. The role of the neurotrophin receptor p75 (p75(NTR)) in the pathogenesis and repair of neonatal excitotoxic brain injury is unknown. Depending on a complex interplay of neurotrophin signalling, p75(NTR) can, in addition to its trophic function, also induce apoptosis.

Hypothesis: We hypothesised that excitotoxicity increases p75(NTR) expression and p75(NTR) 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 p75(NTR) expression in the peri-lesion area. Lesion size was significantly increased in female KO as compared to male KO animals. Knockout of p75(NTR) 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 p75(NTR) expression and caspase-3-activated apoptosis in p75(NTR) KO animals was decreased, we conclude that activation of p75(NTR) 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 p75(NTR) seems to play a dual role.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Brain Injury, Chronic / chemically induced
  • Brain Injury, Chronic / metabolism*
  • Brain Injury, Chronic / pathology
  • Disease Models, Animal
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Neurotoxins / toxicity*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / physiology*


  • Neurotoxins
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nerve Growth Factor
  • TNFRSF16 protein, mouse