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

Feb 13, 2026Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

Psilocybin improves memory for new objects in rats with Fragile X Syndrome by affecting brain growth signaling

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Abstract

Psilocybin microdosing rescued deficits in object recognition memory in a rat model of Fragile X Syndrome (FXS).

Fragile X Syndrome is linked to the loss of a protein crucial for proper brain development.
Serotonergic signaling has been associated with neurodevelopmental impairments in FXS and autism.
The therapeutic effects of psilocybin on memory were not dependent on classical serotonergic receptor activation.
Blocking the TrkB receptor eliminated the memory benefits of psilocybin, suggesting its role in the effects observed.
Psilocybin treatment normalized levels of mature BDNF and TrkB, and restored important signaling pathways in the brain.

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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-exon 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-exon 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. Δ Δ

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

Abstract

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