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Peer-reviewedCC BY-NC-NDTranslational psychiatry

A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome.

  • Lucía de Los Reyes-Ramírez1,2
  • Araceli Bergadà-Martínez2
  • Sara Martínez-Torres2
  • Irene Martínez-Gallego3
  • Pilar Losada-Ruiz3
  • Silvia Arboleya4
  • Antonio González-Matute3
  • Miguel Gueimonde4
  • Rafael Maldonado2,5
  • Antonio Rodríguez-Moreno3
  • Andrés Ozaita6,7
7 affiliations
  1. 1Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
  2. 2Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
  3. 3Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain.
  4. 4Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias, Spanish Research Council (IPLA-CSIC), Oviedo, Spain.
  5. 5IMIM Hospital del Mar Research Institute, Barcelona, Spain.
  6. 6Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. [email protected].
  7. 7Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. [email protected].
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Abstract

Fragile X syndrome (FXS) is the principal monogenic syndrome leading to inherited intellectual disability and autism. It is caused by the silencing of FMR1 gene that leads to the loss in the expression of its encoded protein, the fragile X messenger ribonucleoprotein 1 (FMRP). In synapses, FMRP has a key role in local mRNA modulation to maintain synaptic plasticity. The Fmr1 KO (FX) mouse model shows cognitive impairment and some of the synaptic traits present in individuals with FXS, together with alterations in gut microbiota. Previous studies revealed that pharmacological and genetic cannabinoid type-1 receptor (CB1R) inhibition significantly prevented central key alterations in FX mice. Here, we aimed to evaluate the effect of a sub-chronic treatment with the largely peripherally-restricted CB1R antagonist AM6545. We found that AM6545 reduced memory deficits and restored enhanced hippocampal mGluR5-dependent long-term depression and aberrant dendritic spine density in FX mice. At the peripheral level, AM6545 modified altered FX mice fecal microbiota composition and intestinal Muc2 expression, while in the hippocampus AM6545 treatment upregulated hippocampal Htr4, the gene encoding for serotonin receptor 4 (5-HT4R). This upregulation, also observed in cecum, positively correlated with memory performance. Notably, acute pharmacological blockade of 5-HT4R abolished AM6545 pro-cognitive effect. Our results suggest that repeated peripheral CB1R inhibition ameliorates key central and peripheral alterations in FXS mouse model and modifies the expression of serotonergic receptors important for cognitive performance. Together, this evidence points to the peripheral targeting of CB1R as an approach to alleviate cognitive dysfunction in the FXS context.

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Cite

BibTeXRIS
BibTeX
@article{reyesramirez2026serotonergic,
  title = {{A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome.}},
  author = {Lucía de Los Reyes-Ramírez and Araceli Bergadà-Martínez and Sara Martínez-Torres and Irene Martínez-Gallego and Pilar Losada-Ruiz and Silvia Arboleya and Antonio González-Matute and Miguel Gueimonde and Rafael Maldonado and Antonio Rodríguez-Moreno and Andrés Ozaita},
  journal = {Translational psychiatry},
  year = {2026},
  month = aug,
  doi = {10.1038/s41398-026-04360-4},
  url = {https://europepmc.org/article/MED/42971989},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome.
AU  - Lucía de Los Reyes-Ramírez
AU  - Araceli Bergadà-Martínez
AU  - Sara Martínez-Torres
AU  - Irene Martínez-Gallego
AU  - Pilar Losada-Ruiz
AU  - Silvia Arboleya
AU  - Antonio González-Matute
AU  - Miguel Gueimonde
AU  - Rafael Maldonado
AU  - Antonio Rodríguez-Moreno
AU  - Andrés Ozaita
PY  - 2026
DA  - 2026/08/20
JO  - Translational psychiatry
DO  - 10.1038/s41398-026-04360-4
UR  - https://europepmc.org/article/MED/42971989
AB  - Fragile X syndrome (FXS) is the principal monogenic syndrome leading to inherited intellectual disability and autism. It is caused by the silencing of FMR1 gene that leads to the loss in the expression of its encoded protein, the fragile X messenger ribonucleoprotein 1 (FMRP). In synapses, FMRP has a key role in local mRNA modulation to maintain synaptic plasticity. The Fmr1 KO (FX) mouse model shows cognitive impairment and some of the synaptic traits present in individuals with FXS, together with alterations in gut microbiota. Previous studies revealed that pharmacological and genetic cannabinoid type-1 receptor (CB1R) inhibition significantly prevented central key alterations in FX mice. Here, we aimed to evaluate the effect of a sub-chronic treatment with the largely peripherally-restricted CB1R antagonist AM6545. We found that AM6545 reduced memory deficits and restored enhanced hippocampal mGluR5-dependent long-term depression and aberrant dendritic spine density in FX mice. At the peripheral level, AM6545 modified altered FX mice fecal microbiota composition and intestinal Muc2 expression, while in the hippocampus AM6545 treatment upregulated hippocampal Htr4, the gene encoding for serotonin receptor 4 (5-HT4R). This upregulation, also observed in cecum, positively correlated with memory performance. Notably, acute pharmacological blockade of 5-HT4R abolished AM6545 pro-cognitive effect. Our results suggest that repeated peripheral CB1R inhibition ameliorates key central and peripheral alterations in FXS mouse model and modifies the expression of serotonergic receptors important for cognitive performance. Together, this evidence points to the peripheral targeting of CB1R as an approach to alleviate cognitive dysfunction in the FXS context.
SN  - 2158-3188
ER  -