Psilocybin improves novel object recognition in a rat model of Fragile X Syndrome through the modulation of the BDNF/TrkB signaling pathway
Fabrizio Ascone, Valeria Buzzelli, Francesca Mottarlini, Melania Di Trapano, Paolo Miglioranza, Alessandro Rava, Alessandro Feo, Flavio Spano, Marvin Hausman, Kiminobu Sugaya, Lucia Caffino, Fabio Fumagalli, Viviana Trezza
Neuropsychopharmacology February 13, 2026 DOI: 10.1038/s41386-026-02361-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Fmr1-Δexon 8 rat model of Fragile X Syndrome |
| Intervention | Psilocybin microdosing |
| Topics | Neuroplasticity Psilocybin Serotonin |
| Keywords | Fragile x syndrome Prefrontal cortex Long-term potentiation Signal transduction Postsynaptic potential |
| Citations | 2 |
| Key points | Psilocybin microdosing rescues object recognition memory deficits in a rat model of Fragile X Syndrome via BDNF/TrkB-AKT signaling, not through serotonergic receptor activation. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 5
- Psilocybin restores social novelty investigation in male SAPAP3 knockout mice and engages prefrontal–hippocampal circuitry Molecular Psychiatry September 17, 2026
- Long- term administration of low doses of psilocybin causes epigenetic changes in the rat medial prefrontal cortex Psychopharmacology July 28, 2026
- Therapeutic potential of classic and non-classic psychedelics in neurodevelopmental disorders: Opportunities and challenges Pharmacological Research August 26, 2026
- Classic psychedelics and autism spectrum disorder: preclinical evidence, mechanistic insights and unresolved challenges. Neuroscience & Biobehavioral Reviews August 1, 2026
- Emerging therapeutic opportunities for psychedelic and related drugs. British Journal of Pharmacology July 1, 2026
Cites 27
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 22 more in the library