Psilocybin improves novel object recognition in a rat model of Fragile X Syndrome through the modulation of the BDNF/TrkB signaling pathway
Neuropsychopharmacology – February 13, 2026
Source: OpenAlex
Summary
Psilocybin microdosing significantly improved object recognition memory in a rat model of Fragile X Syndrome (FXS), the leading inherited cause of intellectual disability. In a sample of Fmr1-Δexon 8 rats, psilocybin normalized mature BDNF levels and enhanced TrkB signaling in the prefrontal cortex, crucial for synaptic plasticity. Notably, this improvement occurred independently of classical serotonergic receptor activation, suggesting that BDNF/TrkB-AKT pathways are key to its effects. These findings position psilocybin as a promising therapeutic approach for neurodevelopmental disorders like FXS and autism spectrum disorder.
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.