<b>Fluoxetine and ketamine trigger the p75NTR proteolytic pathway and enhance extinction memory and brain plasticity through p75NTR</b>

<b>Pharmacologically diverse antidepressants were recently described to bind to TrkB and drive a positive allosteric modulation of endogenous BDNF. Although neurotrophins such as BDNF can bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family capable of inducing completely opposite physiological changes, TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Since such qualities were found crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. Indeed, we found that antidepressants like fluoxetine and the fast-acting ketamine also bind to p75NTR, trigger its proteolytic pathway, and induce p75NTR-dependent behavioral/neuroplasticity changes. We suggest that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain ability for remodeling.</b>