Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway

TY - JOUR

T1 - Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway

AU - Diniz, Cassiano R A F

AU - Crestani, Ana Paula

AU - C Casarotto, Plinio

AU - Biojone, Caroline

AU - Cannarozzo, Cecilia

AU - Winkel, Frederike

AU - Prozorov, Mikhail A

AU - Kot, Erik F

AU - Goncharuk, Sergey A

AU - Benette Marques, Danilo

AU - Zacharias, Leonardo R

AU - Autio, Henri

AU - Pryiadrashini Sahu, Madhusmita

AU - Borges-Assis, Anna Barbara

AU - Pereira Leite, Joao

AU - Mineev, Konstantin S.

AU - Castren, Eero

AU - Resstel, L B M

PY - 2025/2/1

Y1 - 2025/2/1

N2 - Background: Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), 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 crosslike conformation dimer and carry a cholesterol-recognition amino acid consensus in the transmembrane domain. As such qualities were found to be crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. Methods: Enzyme-linked immunosorbent assay–based binding and nuclear magnetic resonance spectroscopy were performed to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to investigate whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase–dependent p75NTR proteolysis and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75NTR knockout mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verify how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male wild-type mice and rats. Results: Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. Conclusions: We hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain's ability for remodeling.

AB - Background: Diverse antidepressants were recently described to bind to TrkB (tyrosine kinase B) and drive a positive allosteric modulation of endogenous BDNF (brain-derived neurotrophic factor). Although neurotrophins such as BDNF can bind to p75NTR (p75 neurotrophin receptor), 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 crosslike conformation dimer and carry a cholesterol-recognition amino acid consensus in the transmembrane domain. As such qualities were found to be crucial for antidepressants to bind to TrkB and drive behavioral and neuroplasticity effects, we hypothesized that their effects might also depend on p75NTR. Methods: Enzyme-linked immunosorbent assay–based binding and nuclear magnetic resonance spectroscopy were performed to assess whether antidepressants would bind to p75NTR. HEK293T cells and a variety of in vitro assays were used to investigate whether fluoxetine (FLX) or ketamine (KET) would trigger any α- and γ-secretase–dependent p75NTR proteolysis and lead to p75NTR nuclear localization. Ocular dominance shift was performed with male and female p75NTR knockout mice to study the effects of KET and FLX on brain plasticity, in addition to pharmacological interventions to verify how p75NTR signaling is important for the effects of KET and FLX in enhancing extinction memory in male wild-type mice and rats. Results: Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. Conclusions: We hypothesize that antidepressants co-opt both BDNF/TrkB and proBDNF/p75NTR systems to induce a more efficient activity-dependent synaptic competition, thereby boosting the brain's ability for remodeling.

KW - Antidepressants

KW - Binding

KW - Extinction memory

KW - Fluoxetine

KW - Ketamine

KW - Neuroplasticity

KW - p75NTR proteolysis

KW - proBDNF

UR - http://www.scopus.com/inward/record.url?scp=85202481413&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2024.06.021

DO - 10.1016/j.biopsych.2024.06.021

M3 - Journal article

C2 - 38945387

SN - 0006-3223

VL - 97

SP - 248

EP - 260

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 3

ER -