p75 neurotrophin receptor expression defines a population of BDNF-responsive neurogenic precursor cells

Although our understanding of adult neurogenesis has increased dramatically over the last decade, confusion still exists regarding both the identity of the stem cell responsible for neuron production and the mechanisms that regulate its activity. Here we show, using flow cytometry, that a small population of cells (0.3%) within the stem cell niche of the rat subventricular zone (SVZ) expresses the p75 neurotrophin receptor (p75(NTR)) and that these cells are responsible for neuron production in both newborn and adult animals. In the adult, the p75(NTR)-positive population contains all of the neurosphere-producing precursor cells, whereas in the newborn many of the precursor cells are p75(NTR) negative. However, at both ages, only the neurospheres derived from p75(NTR)-positive cells are neurogenic. We also show that neuron production from p75(NTR)-positive but not p75(NTR)-negative precursors is greatly enhanced after treatment with brain-derived neurotrophic factor (BDNF) or nerve growth factor. This effect appears to be mediated specifically by p75(NTR), because precursor cells from p75(NTR)-deficient mice show a 70% reduction in their neurogenic potential in vitro and fail to respond to BDNF treatment. Furthermore, adult p75(NTR)-deficient mice have significantly reduced numbers of PSA-NCAM (polysialylated neural cell adhesion molecule)-positive SVZ neuroblasts in vivo and a lower olfactory bulb weight. Thus, p75(NTR) defines a discrete population of highly proliferative SVZ precursor cells that are able to respond to neurotrophin activation by increasing neuroblast generation, making this pathway the most likely mechanism for the increased neurogenesis that accompanies raised BDNF levels in a variety of disease and behavioral situations.