Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway.
Cassiano Ricardo Alves Faria Diniz, Ana Paula Crestani, Plinio Cabrera Casarotto, Caroline Biojone, Cecilia Cannarozzo, Frederike Winkel, Mikhail A Prozorov, Erik F. Kot, Sergey A. Goncharuk, Danilo Benette Marques, Leonardo Rakauskas Zacharias, Henri Autio, Madhusmita Priyadarshini Sahu, Anna Bárbara Borges-Assis, João Pereira Leite, Konstantin S Mineev, Eero Castrén, Leonardo Barbosa Moraes Resstel
Biological Psychiatry February 1, 2025 DOI: 10.1016/j.biopsych.2024.06.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with in vitro assays, behavioral tests, and knockout mouse models Peer reviewed |
|---|---|
| Population | HEK293T cells, male and female p75NTR knockout mice, male wild-type mice and rats |
| Interventions | Fluoxetine Ketamine |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Binding Extinction memory Fluoxetine P75ntr proteolysis Probdnf Antidepressants ssris Mood stabilizers Psychiatric medications Neuroscience brain science Neural studies Neurobiology Memory extinction Cognitive processing Brain plasticity neuroplast |
| Citations | 15 |
| Key findings | Antidepressants bind to p75NTR and trigger p75NTR-dependent proteolysis, neuroplasticity, and extinction memory enhancement. |
Abstract
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. 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. Antidepressants were found to bind to p75NTR. FLX and KET triggered the p75NTR proteolytic pathway and induced p75NTR-dependent behavioral/neuroplasticity changes. 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.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 5
- Synaptic priming: A framework for pharmacotherapy in depression. Neuron November 19, 2025
- The transformational power of psychedelics: catalysts for creativity, consciousness, and mental health. Molecular Psychiatry September 30, 2025
- Transcriptional profiles of antidepressant resistance across the corticolimbic pathway of chronically stressed mice. Neuropsychopharmacology June 1, 2026
- A time-sensitive plasticity distinguishes the rapid and sustained synaptic actions of ketamine from its (2R,6R)-hydroxynorketamine metabolite. Journal of Neuroscience February 3, 2026
- Where is the sweet spot for psychedelic-enhanced fear extinction? An integrative quantitative synthesis of dose-effect patterns in rodent models. Journal of Psychopharmacology August 3, 2026
Cites 2
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and its metabolite 2R,6R‐hydroxynorketamine promote ocular dominance plasticity and release tropomyosin‐related kinase B from inhibitory control without reducing perineuronal nets enwrapping parvalbumin interneurons March 1, 2023