{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.",
    "Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.",
    "Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Seville, Spain.",
    "Department of Microbiology and Biochemistry of Dairy Products, Instituto de Productos Lácteos de Asturias, Spanish Research Council (IPLA-CSIC), Oviedo, Spain.",
    "IMIM Hospital del Mar Research Institute, Barcelona, Spain.",
    "Research Group in Biology of Cognition, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. andres.ozaita@upf.edu.",
    "Laboratory of Neuropharmacology-NeuroPhar, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain. andres.ozaita@upf.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Lucía de Los Reyes-Ramírez",
      "orcid": "0000-0001-7880-1199"
    },
    {
      "affs": [
        1
      ],
      "name": "Araceli Bergadà-Martínez"
    },
    {
      "affs": [
        1
      ],
      "name": "Sara Martínez-Torres"
    },
    {
      "affs": [
        2
      ],
      "name": "Irene Martínez-Gallego"
    },
    {
      "affs": [
        2
      ],
      "name": "Pilar Losada-Ruiz"
    },
    {
      "affs": [
        3
      ],
      "name": "Silvia Arboleya"
    },
    {
      "affs": [
        2
      ],
      "name": "Antonio González-Matute"
    },
    {
      "affs": [
        3
      ],
      "name": "Miguel Gueimonde"
    },
    {
      "affs": [
        1,
        4
      ],
      "name": "Rafael Maldonado",
      "orcid": "0000-0002-4359-8773"
    },
    {
      "affs": [
        2
      ],
      "name": "Antonio Rodríguez-Moreno",
      "orcid": "0000-0002-8078-6175"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Andrés Ozaita",
      "orcid": "0000-0002-2239-7403"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8pjtewde3kaxe.bib",
  "cited_by": 0,
  "doi": "10.1038/s41398-026-04360-4",
  "fulltext_url": "https://europepmc.org/articles/PMC13728186",
  "id": "8pjtewde3kaxe",
  "issns": [
    "2158-3188"
  ],
  "landing_url": "https://europepmc.org/article/MED/42971989",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
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      "openalex",
      "1311|Genetics and Neurodevelopmental Disorders"
    ]
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  "openalex": "W4406818926",
  "pdf_url": "https://europepmc.org/articles/PMC13728186?pdf=render",
  "pmcid": "PMC13728186",
  "pmid": "42971989",
  "published": "2026-08-20",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/8pjtewde3kaxe.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:44Z",
      "native_id": "MED:42971989",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42971989"
    },
    {
      "first_seen": "2026-11-06T12:23:55Z",
      "native_id": "PMC13728186",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41398-026-04360-4"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genetics and Neurodevelopmental Disorders",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome.",
  "title_text": "A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:23:55Z",
  "url": "https://research.draconitic.com/paper/8pjtewde3kaxe",
  "venue": "Translational psychiatry",
  "versions": []
}