A novel p75NTR signaling pathway promotes survival, not death, of immunopurified neocortical subplate neurons

Subplate neurons of mammalian neocortex undergo pronounced cell death postn atally, long after they have matured and become incorporated into functiona l cortical circuits. They express the p75 neurotrophin receptor (p75NTR), w hich is known to signal cell death in some types of neurons via the activat ion of sphingomyelinase and the concomitant increase in the sphingolipid ce ramide. To evaluate the role of p75NTR in subplate neurons, they were immun opurified and cultured in vitro. Contrary to its known function as a death receptor, ligand binding to p75NTR promotes subplate neuron survival. Moreo ver, p75NTR-dependent survival is blocked by inhibition of ceramide synthes is and rescued by addition of its precursor sphingomyelin. Inhibition of Tr k signaling does not block survival, nor is Trk signaling alone sufficient to promote survival. Thus, ligand-dependent p75NTR regulation of the cerami de pathway mediates survival in certain neurons and may represent an import ant target for neuroprotective drugs in degenerative diseases involving p75 NTR-expressing neurons, such as Alzheimer's disease.