Psilocybin improves novel object recognition in a rat model of Fragile X Syndrome through the modulation of the BDNF/TrkB signaling pathway

  • Neuropsychopharmacology. 2026 Jul;51(8):1454-1463. doi: 10.1038/s41386-026-02361-x.
Fabrizio Ascone  #  1 ,  Valeria Buzzelli  #  1 ,  Francesca Mottarlini  2 ,  Melania Di Trapano  1 ,  Paolo Miglioranza  2 ,  Alessandro Rava  1  3 ,  Alessandro Feo  1 ,  Flavio Spano  1 ,  Marvin Hausman  4 ,  Kiminobu Sugaya  5 ,  Lucia Caffino  2 ,  Fabio Fumagalli  2 ,  Viviana Trezza  6  7
Affiliations
  • 1. Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Rome, Italy.
  • 2. Department of Pharmacological and Biomolecular Sciences 'Rodolfo Paoletti', Università degli Studi di Milano, Milan, Italy.
  • 3. Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy.
  • 4. Nova Mentis Life Science Corp., Vancouver, BC, Canada.
  • 5. Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
  • 6. Department of Science, Section of Biomedical Sciences and Technologies, University "Roma Tre", Rome, Italy. [email protected].
  • 7. Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy. [email protected].
  • # Contributed equally.
PMID: 41688761 DOI: 10.1038/s41386-026-02361-x
Abstract

Fragile X Syndrome (FXS) is the most common inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). As a synaptic disorder, FXS involves the loss of Fragile X messenger ribonucleoprotein 1 (FMRP), leading to abnormal dendrite development and immature dendritic spines. Serotonergic signaling, essential for neuronal development and circuit remodeling, has been implicated in ASD and related conditions, including FXS, raising the possibility that serotonergic modulation could ameliorate neurodevelopmental impairments. This study investigated the therapeutic potential of psilocybin, a serotonergic compound, in the validated Fmr1-Δexon 8 rat model of FXS. Psilocybin microdosing rescued deficits in NOR. Importantly, its benefits on recognition memory persisted despite pretreatment with the 5HT2AR antagonist, volinanserin, or the 5HT1AR antagonist, WAY-100635, indicating that classical serotonergic receptor activation is not required. In contrast, pretreatment with the TrkB receptor antagonist, ANA-12, abolished psilocybin's effects, implicating BDNF/TrkB signaling as essential. At the molecular level, psilocybin normalized mature BDNF (mBDNF), increased TrkB, and restored downstream Akt signaling in the prefrontal cortex of Fmr1-Δexon 8 rats, pathways strongly linked to synaptic plasticity and cognitive function. These findings demonstrate that psilocybin rescues object recognition memory deficits in this rat model of FXS via BDNF/TrkB-AKT signaling rather than serotonergic receptor mechanisms. By dissociating therapeutic effects from hallucinogenic pathways, our results highlight psilocybin microdosing as a promising therapeutic strategy for neurodevelopmental disorders such as FXS and ASD.

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