Volosin M, Song W, Almeida RD, Kaplan DR, Hempstead BL, Friedman WJ. The p75 neurotrophin receptor (p75NTR) and Trk receptor tyrosine kinases elicit opposite cellular consequences: apoptosis and survival, respectively. This week, Volosin et al. compared the actions of proneurotrophins, selective activators of p75NTR, with neurotrophins on basal forebrain neurons. These cholinergic neurons express p75NTR throughout life as well as all three Trk receptors. The results suggest that Trk receptor activation cannot overcome apoptosis triggered by activation of p75NTR in these cells. Forty percent of cultured basal forebrain neurons died after treatment with pro-nerve growth factor (pro-NGF), but not after mature NGF treatment. Pro-NGF-induced apoptosis required p75NTR and its coreceptor sortilin. After kainic acid-induced seizures, pro-NGF was detected in basal forebrain astrocytes, lysates from these animals induced cell death of cultured basal forebrain neurons, and neuronal loss was less in p75-/- mice. In contrast to previous studies in sympathetic ganglion neurons, activation of Trk receptors did not protect against pro-NGF-mediated apoptosis.