Involvement of the p75^NTR signaling pathway in persistent synaptic suppression coupled with synapse elimination following repeated long-term depression induction

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.