Survival of Cholinergic Forebrain Neurons in Developing p75 ^NGFR -Deficient Mice

Abstract

The functions of the low-affinity p75 nerve growth factor receptor (p75(NGFR)) in the central nervous system were explored in vivo. In normal mice, approximately 25 percent of the cholinergic basal forebrain neurons did not express TrkA and died between postnatal day 6 and 15. This loss did not occur in p75(NGFR)-deficient mice or in normal mice systemically injected with a p75(NGFR)-inhibiting peptide. Control, but not p75(NGFR)-deficient, mice also had fewer cholinergic striatal interneurons. Apparently, p75(NGFR) mediates apoptosis of these developing neurons in the absence of TrkA, and modulation of p75(NGFR) can promote neuronal survival. Cholinergic basal forebrain neurons are involved in learning and memory.

Neurotrophins: the biological paradox of survival factors eliciting apoptosis

“…Analysis of mice has also revealed a significantly higher number of cholinergic neurons in the basal forebrain in p75 7/7 mice compared to wild type controls (Van der Zee et al, 1996;Yeo et al, 1997). These observations indicate that the absence of p75 resulted in enhanced survival, similar to the antisense effects observed in postnatal sensory neurons (Barrett and Bartlett, 1994).…”

A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA

“…p75 NTR also initiates signal transduction separately from TrkA (55)(56)(57). There is increasing evidence that the signals generated by p75 NTR promote programmed cell death (58)(59)(60)(61) rather than prevent it, as does TrkA (62). p75 NTR is internalized and retrogradely transported, but it does not appear to be down-regulated from the cell surface in response to NGF (M.G., D. Hall, A. Schroepfel, and W.M., unpublished observations) (63)(64)(65).…”

Life and death decisions: a biological role for the p75 neurotrophin receptor

“…The most compelling case that it does, to at least some degree, derives from recent studies on basal forebrain cholinergic neurons; in the p75 NTR7/7 mice, the number of basal forebrain cholinergic neurons is increased (Van der Zee et al, 1996), and the innervation is perturbed (Yeo et al, 1997), phenotypes reminiscent of those observed for p75 NTR7/7 sympathetic neurons. Moreover, a p75 NTR -mediated death signal may become important in situations of neuronal stress and/or injury.…”