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Psilocybin mitigates the cognitive deficits observed in a rat model of Fragile X syndrome

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Abstract

Rationale

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and the leading monogenic cause of autism spectrum disorder (ASD). Serotonergic neurotransmission has a key role in the modulation of neuronal activity during development, and therefore, it has been hypothesized to be involved in ASD and co-occurring conditions including FXS. As serotonin is involved in synaptic remodeling and maturation, serotonergic insufficiency during childhood may have a compounding effect on brain patterning in neurodevelopmental disorders, manifesting as behavioral and emotional symptoms. Thus, compounds that stimulate serotonergic signaling such as psilocybin may offer promise as effective early interventions for developmental disorders such as ASD and FXS.

Objectives

The aim of the present study was to test whether different protocols of psilocybin administration mitigate cognitive deficits displayed by the recently validated Fmr1-Δexon 8 rat model of ASD, which is also a model of FXS.

Results

Our results revealed that systemic and oral administration of psilocybin microdoses normalizes the aberrant cognitive performance displayed by adolescent Fmr1-Δexon 8 rats in the short-term version of the novel object recognition test—a measure of exploratory behavior, perception, and recognition.

Conclusions

These data support the hypothesis that serotonin-modulating drugs such as psilocybin may be useful to ameliorate ASD-related cognitive deficits. Overall, this study provides evidence of the beneficial effects of different schedules of psilocybin treatment in mitigating the short-term cognitive deficit observed in a rat model of FXS.

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Funding

The study was funded by NOVA MENTIS Life Science Corp., by PRIN 2017 grant (2017SXEXT5) by MIUR (Viviana Trezza), and by Regione Lazio “Gruppi di ricerca 2020” grant # PROT. A0375-2020–36550 (Viviana Trezza).

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Author notes

  1. Valeria Buzzelli and Emilia Carbone contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Science, Section of Biomedical Sciences and Technologies, University “Roma Tre”, Viale G. Marconi 446, 00146, Rome, Italy

    Valeria Buzzelli, Emilia Carbone, Antonia Manduca, Sara Schiavi, Alessandro Feo & Viviana Trezza

  2. Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy

    Antonia Manduca

  3. Nova Mentis Life Science Corp., Vancouver, BC, Canada

    Julia V. Perederiy, Kyle H. Ambert & Marvin Hausman

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  1. Valeria Buzzelli
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Contributions

V.B. and E.C. performed, analyzed, and contributed to the design of the behavioral experiments. A.M., S.S. and A.F. contributed to the behavioral experiments. V.B., E.C., A.M., and J.V.P. wrote the manuscript. K.H.A. contributed to the statistical analysis of the behavioral data. M.H. contributed to the design of the experiments. V.T. supervised the project, designed the experiments, and wrote, revised, and edited the manuscript.

Corresponding author

Correspondence to Viviana Trezza.

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Conflict of interest

Valeria Buzzelli, Emilia Carbone, Antonia Manduca, Sara Schiavi, Alessandro Feo, and Viviana Trezza have no conflict of interest. Julia V. Perederiy, Kyle H. Ambert, and Marvin Hausman are employees of NOVA MENTIS Life Science Corp.

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Supplementary Fig. 1

Experimental setting of the short-term novel object recognition (NOR) task. We used a grey square arena (40 × 40 × 10 cm; l × w × h) for all the three phases of the task: during the habituation phase (A), the animal was individually placed in the middle of the empty arena for 5 minutes; subsequently, in the training phase (B), two identical objects were positioned inside the arena, allowing the animal to explore them for 5 minutes; 30 minutes after the training phase, the test session took place (C), where one copy of the familiar object (“old”) and a new object (“new”) were placed inside the arena and the animal was free to explore them for 5 min. (PNG 1894 kb)

High resolution image (TIFF 19779 kb)

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Buzzelli, V., Carbone, E., Manduca, A. et al. Psilocybin mitigates the cognitive deficits observed in a rat model of Fragile X syndrome. Psychopharmacology 240, 137–147 (2023). https://doi.org/10.1007/s00213-022-06286-3

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