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

Abstract

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.

Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment

“…The role of the hippocampus in extinction has also been demonstrated by Barnes et al (2008) who have shown that inhibition of proBDNF cleavage in the CA1 region facilitates extinction (Barnes and Thomas, 2008). ProBDNF signaling via the p75 receptor facilitates long-term depression which could underlie the extinction process (Egashira et al, 2010). In this regard, it is worth noting that we observed in adult BDNF HET rats levels of proBDNF in the hippocampus that were comparable to WT levels.…”

Chondroitin Sulfate Proteoglycans Down-regulate Spine Formation in Cortical Neurons by Targeting Tropomyosin-related Kinase B (TrkB) Protein

“…For example, p75NTR-deficient mice have a higher spine density than wild-type mice, and conversely, p75NTR overexpression in wild-type neurons decreases spine density (15). A high affinity ligand for p75NTR, pro-BDNF, eliminates dendritic spines via p75NTR (16). In this study, we showed that BDNF decreased dendritic spine density when CSPGs were added and that this effect was attenuated by neutralization by anti-p75NTR antibody (Fig.…”

“…TrkB promotes dendritic spine formation (10), p75NTR, another BDNF receptor, mediates spine elimination (15,16). Thus, we investigated whether p75NTR is involved in decreased spine formation elicited by CSPGs in BDNF-treated neurons.…”

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…In fact, altered expression of AMPA receptor subunits is observed in the hippocampus of p75 NTR knockout mice (61). Second, p75 NTR acts as a negative regulator of dendritic spine density and morphology (24,75). Accordingly, KI mutant mice show a significant loss of dendritic spines in CA1 pyramidal neurons, a phenotype recovered by normalization of p75 NTR levels, suggesting that synaptic and memory deficits in HD could be related to a reduction in the number and complexity of hippocampal dendritic spines.…”