Mj. Courtney et al., NEUROTROPHINS PROTECT CULTURED CEREBELLAR GRANULE NEURONS AGAINST THEEARLY PHASE OF CELL-DEATH BY A 2-COMPONENT MECHANISM, The Journal of neuroscience, 17(11), 1997, pp. 4201-4211
Cerebellar granule neurons cultured with serum develop a mature neuron
al phenotype, including stimulus-coupled release of glutamate, and dep
end on elevated potassium for survival. We find that cells cultured wi
th serum undergo two phases of cell death. By 6 d in vitro, 30-50% of
the cells present are dead; after this time the remaining cells die. E
levated potassium prevents only this later phase of death, whereas neu
rotrophins protect these cells against the early phase of death. Facto
rs that bind p75(NTR) Or TNF-R, members of the same receptor family, e
xhibit voltage-sensitive calcium channel-dependent protection, whereas
ligands of expressed Trk receptors show additional calcium channel-in
dependent protection. The cells express TrkB protein and show elevated
c-Fos and c-Jun levels in response to BDNF. No TrkA is detected, alth
ough p75(NTR) protein is expressed and NGF induces depolarization-depe
ndent elevation of c-Jun levels. In the presence of the protein kinase
C inhibitor bisindolylmaleimide, BDNF-induced survival promotion is r
educed partially, whereas NGF-induced death is unmasked. Basal surviva
l mechanisms are insensitive to inhibition of PK-C or PI-3 kinase. We
conclude that BDNF promotes survival in part via its TrkB receptor, wh
ereas there is an additional pathway promoting survival and elevating
c-Jun evoked by both NGF and BDNF via a non-Trk receptor.