Endogenous brain-derived neurotrophic factor and neurotrophin-3 antagonistically regulate survival of axotomized corticospinal neurons in vivo

Neuronal growth factors regulate the survival of neurons by their survival and death- promoting activity on distinct populations of neurons. The neuro trophins nerve growth factor (NGF), brain- derived neurotrophic factor (BDN F), and neurotrophin- 3 (NT- 3) promote neuronal survival via tyrosine kina se (Trk) receptors, whereas NGF and BDNF can also induce apoptosis in devel oping neurons through p75(NTR) receptors in the absence of their respective Trk receptors. Using mutant mice and inactivation of neurotrophins and the ir receptors with antibodies in rats, we show that endogenous NT- 3 induces death of adult BDNF- dependent, axotomized corticospinal neurons (CSNs). W hen NT- 3 is neutralized, the neurons survive even without BDNF, suggesting complete antagonism. Whereas virtually all unlesioned and axotomized CSNs express both trkB and trkC mRNA, p75 is barely detectable in unlesioned CSN s but strongly upregulated in axotomized CSNs by day 3 after lesion, the ti me point when cell death occurs. Blocking either cortical TrkC or p75(NTR) receptors alone prevents death, indicating that the opposing actions of NT- 3 and BDNF require their respective Trk receptors, but induction of death depends on p75(NTR) cosignaling. The results show that neuronal survival ca n be regulated antagonistically by neurotrophins and that neurotrophins can induce neuronal death in the adult mammalian CNS. We further present evide nce that signaling of tyrosine kinase receptors of the trk family can be cr ucially involved in the promotion of neuronal death in vivo.