TrkB mediates BDNF-induced potentiation of neuronal necrosis in cortical culture.
In the present study, the signaling mechanisms underlying the effect of brain-derived neurotrophic factor (BDNF) on neuronal necrosis were investigated. Exposure of mature mouse cortical cultures (more than 10 days in vitro (DIV)) to 50-100 ng/ml BDNF for 48 h induced widespread neuronal necrosis that was antioxidant-sensitive. This neuronal necrosis was blocked by the selective NMDA antagonist MK-801, suggesting that prolonged BDNF exposure caused endogenous levels of NMDA receptor activation to become excitotoxic. We examined whether the p75(NTR) played a role in BDNF-induced neuronal death. However, p75(NTR) expression was low in cultured cortical cells, and neutralizing antibodies to p75(NTR) did not attenuate BDNF-triggered neuronal death. In contrast, trkB antisense oligonucleotides and inhibitors of Trk tyrosine kinase blocked BDNF-triggered neuronal death as well as BDNF potentiation of iron-induced oxidative neuronal necrosis, suggesting a critical role for TrkB in this phenomenon. Furthermore, BDNF did not potentiate neuronal necrosis in cortical cultures prepared from embryonic TrkB-null mice. These results suggest that TrkB plays an important role in BDNF-mediated neuronal necrosis.
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB