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Cited by 13Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Dysregulation of the mTOR-FMRP pathway and synaptic plasticity in an environmental model of ASD

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Hilal, Muna L., Rosina, Eleonora, Pedini, Giorgia, Restivo, Leonardo, Bagni, Claudia·2025·Molecular Psychiatry
DOI 10.1038/s41380-024-02805-0PMC PMC12014490
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Abstract

Autism Spectrum Disorder (ASD) is caused by genetic, epigenetic, and environmental factors. Mutations in the human FMR1 gene, encoding the Fragile X Messenger Ribonucleoprotein 1 (FMRP), cause the most common monogenic form of ASD, the Fragile X Syndrome (FXS). This study explored the interaction between the FMR1 gene and a viral-like infection as an environmental insult, focusing on the impact on core autistic-like behaviors and the mGluR1/5-mTOR pathway. Pregnant heterozygous Fmr1 mouse females were exposed to maternal immune activation (MIA), by injecting the immunostimulant Poly (I:C) at the embryonic stage 12.5, simulating viral infections. Subsequently, ASD-like behaviors were analyzed in the adult offspring, at 8–10 weeks of age. MIA exposure in wild-type mice led to ASD-like behaviors in the adult offspring. These effects were specifically confined to the intrauterine infection, as immune activation at later stages, namely puberty (Pubertal Immune Activation, PIA) at post-natal day 35 or adulthood (Adult Immune Activation, AIA) at post-natal day 56, did not alter adult behavior. Importantly, combining the Fmr1 mutation with MIA exposure did not intensify core autistic-like behaviors, suggesting an occlusion effect. Mechanistically, MIA provided a strong activation of the mGluR1/5-mTOR pathway, leading to increased LTP and downregulation of FMRP specifically in the hippocampus. Finally, FMRP modulates mTOR activity via TSC2. These findings further strengthen the key role of the mGluR1/5-mTOR pathway in causing ASD-like core symptoms.

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  • FMR1 encodes FMRP, an RNA-binding protein that binds to multiple mRNAs and inhibits or finely regulates local translation at synapses.

    “FMR1 encodes the fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein that binds to multiple mRNAs. Its primary function is to inhibit or finely regulate the local translation of these mRNAs at synapses (Hilal et al., 2025).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Hilal et al., 2025

    The Introduction identifies FMR1 as encoding FMRP, calls FMRP an RNA-binding protein, and describes its many mRNA targets. The Discussion says FMRP regulates mRNA translation, but our copy does not specify that its primary function is to inhibit translation or that this regulation occurs locally at synapses. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Partial disruption of FMRP function or RNA-mediated toxicity can alter neural circuits sufficiently to produce core autistic traits without triggering the full syndromic phenotype.

    “These observations indicate that partial disruption of FMRP function or RNA-mediated toxicity can alter neural circuits sufficiently to produce core autistic traits without triggering the full syndromic phenotype (Hilal et al., 2025).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Hilal et al., 2025

    The Results report a 20% reduction in hippocampal FMRP in wild-type mice exposed to maternal immune activation, and the Discussion links that exposure to core autistic-like behaviors and altered synaptic plasticity. The paper does not identify RNA-mediated toxicity as a mechanism or establish that the mice lacked the full syndromic phenotype; it reports only that certain associated comorbidities were absent. The evidence is from a mouse model, not a demonstration about autistic traits in people. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Hilal, M. L., Rosina, E., Pedini, G., Restivo, L., & Bagni, C.
Affiliations
  • University of Lausanne (CH)
  • University of Rome Tor Vergata (IT)
Corresponding author
Bagni, Claudia
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2024-11-27
Volume
30
Issue
5
Pages
1937-1951
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-024-02805-0
PMC
PMC12014490
OpenAlex
W4404768759
Cited by
13
References
7
Citations by year
2026: 7 · 2025: 5 · 2024: 1
FWCI
3.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, cc-by)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, cc-by-nc-nd)
  • IRIS (submittedVersion, cc-by)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030-182651, NCCR Synapsy 51NF40-158776)
  • Fondazione Telethon (GGP20137)
  • MUR-PRIN2017
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, fragile X syndrome, FMRP, mTOR signaling, maternal immune activation, poly(I:C), environmental risk factors, synaptic plasticity, long-term potentiation, hippocampus, TSC2, autism-like behavior, intrauterine infection
MeSH terms
Autism Spectrum Disorder, Animals, Disease Models, Animal, Female, Fragile X Syndrome, Hippocampus, Male, Mice, Inbred C57BL, Neuronal Plasticity, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Signal Transduction, Receptors, Metabotropic Glutamate, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, TOR Serine-Threonine Kinases, Receptor, Metabotropic Glutamate 5

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