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The Journal of Neuroscience, July 15, 2001, 21(14):5121-5129

A Novel p75NTR Signaling Pathway Promotes Survival, Not Death, of Immunopurified Neocortical Subplate Neurons

Michael F. DeFreitas¹, Patrick S. McQuillen², and Carla J. Shatz¹

¹ Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and ² Department of Pediatrics, University of California, San Francisco Medical Center, San Francisco, California 94143

Subplate neurons of mammalian neocortex undergo pronounced cell death postnatally, long after they have matured and become incorporated into functional cortical circuits. They express the p75 neurotrophin receptor (p75NTR), which is known to signal cell death in some types of neurons via the activation of sphingomyelinase and the concomitant increase in the sphingolipid ceramide. To evaluate the role of p75NTR in subplate neurons, they were immunopurified and cultured in vitro. Contrary to its known function as a death receptor, ligand binding to p75NTR promotes subplate neuron survival. Moreover, p75NTR-dependent survival is blocked by inhibition of ceramide synthesis and rescued by addition of its precursor sphingomyelin. Inhibition of Trk signaling does not block survival, nor is Trk signaling alone sufficient to promote survival. Thus, ligand-dependent p75NTR regulation of the ceramide pathway mediates survival in certain neurons and may represent an important target for neuroprotective drugs in degenerative diseases involving p75NTR-expressing neurons, such as Alzheimer's disease.

Key words: subplate neurons; p75 neurotrophin receptor; survival; ceramide; BDNF; immunopurification

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21145121-09$05.00/0

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