Neurotrophins are involved in the modulation of synaptic transmission, including the induction of long-term potentiation (LTP) through the receptor TrkB. Because previous studies have revealed a bidirectional mode of neurotrophin action by virtue of signaling through either the neurotrophin receptor p75^NTR or the Trk receptors, we tested the hypothesis that p75^NTR is important for longterm depression (LTD) to occur. Although LTP was found to be unaffected in hippocampal slices of two different strains of mice carrying mutations of the p75^NTR gene, hippocampal LTD was impaired in both p75^NTR-deficient mouse strains. Furthermore, the expression levels of two (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits, GluR2 and GluR3, but not GluR1 or GluR4, were found to be significantly altered in the hippocampus of p75^NTR-deficient mice. These results implicate p75^NTR in activity-dependent synaptic plasticity and extend the concept of functional antagonism of the neurotrophin signaling system.