Synaptic plasticity, especially structural plasticity, is thought to be a basis for long‐lasting memory. We previously reported that, in rat hippocampus slice cultures, repeated induction of long‐term depression (LTD) by application of a metabotropic glutamate receptor (mGluR) agonist led to slowly developing, long‐lasting synaptic suppression coupled with synapse elimination. We referred to this phenomenon as LOSS (LTD‐repetition‐operated synaptic suppression) to discriminate it from conventional single LTD and proposed it as a model for analyzing structural plasticity. Recently, proneurotrophin‐activated p75^NTR signaling has been gaining attention as a possible pathway for the regulation of both neuronal apoptosis and synaptic plasticity. In this study, we examined whether this signaling has a role in the establishment of LOSS. The application of anisomycin indicated that, for LOSS to occur, novel protein synthesis is needed within 6 hr after the induction of mGluR‐dependent LTD, which demonstrates that LOSS is an active process and therefore is not due to withering in response to a shortage of trophic factors. Furthermore, we found that pro‐BDNF (a species of proneurotrophins) is newly synthesized within 6 hr after the induction of LTD. We therefore exogenously applied a cleavage‐resistant form of pro‐BDNF, finding synaptic suppression similar to LOSS. LOSS could be abolished by the application of an antibody that binds to and neutralizes p75^NTR following repeated LTD induction. These results suggest involvement of the p75^NTR signaling pathway in the long‐lasting decremental form of synaptic plasticity. © 2010 Wiley‐Liss, Inc.