Data set

Pharmacologically diverse antidepressants were recently described to directly bind to TrkB and drive a positive allosteric modulation of endogenous BDNF action, thus promoting neuronal activity-dependent synaptic plasticity. Although neurotrophins such as BDNF can still bind to the p75 neurotrophin receptor (p75NTR), their precursors are the high affinity p75NTR ligands. While part of an unrelated receptor family, inducing even completely opposite physiological changes, both TrkB and p75NTR feature a cross-like conformation dimer and carry a cholesterol-recognition and alignment consensus in the transmembrane domain. Once such qualities were found crucial for the antidepressants to bind to TrkB and drive their behavioral and plasticity effects, we hypothesized that their effect 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 thus 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.