Activation of TrkB receptors by brain-derived neurotrophic factor (BDNF) followed by MAPK/ERK signaling increases dendritic spine density and the proportion of mature spines in hippocampal CA1 pyramidal neurons. Considering the opposing actions of p75NTR and Trk receptors in several BDNF actions on CNS neurons, we tested whether these receptors also have divergent actions on dendritic spine density and morphology. A function-blocking anti- p75NTR antibody (REX) did not affect spine density by itself but it prevented BDNF's effect on spine density. Intriguingly, REX by itself increased the proportion of immature spines and prevented BDNF's effect on spine morphology. In contrast, the Trk receptor inhibitor k-252a increased spine density by itself, and prevented BDNF from further increasing spine density. However, most of the spines in k-252a-treated slices were of the immature type. These effects of k-252a on spine density and morphology required neuronal activity because they were prevented by TTX. These divergent BDNF actions on spine density and morphology are reminiscent of opposing functional signaling by p75NTR and Trk receptors and reveal an unexpected level of complexity in the consequences of BDNF signaling on dendritic morphology. © 2012 Christopher A. Chapleau and Lucas Pozzo-Miller.