Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid
Open accessAbstract
BACKGROUND: The molecular mechanisms underlying autistic behaviors remain to be elucidated. Mutations in genes linked to autism adversely affect molecules regulating dendritic spine formation, function and plasticity, and some increase the mammalian target of rapamycin, mTOR, a regulator of protein synthesis at spines. Here, we investigated whether the Akt/mTOR pathway is disrupted in idiopathic autism and in rats exposed to valproic acid, an animal model exhibiting autistic-like behavior. METHODS: Components of the mTOR pathway were assayed by Western blotting in postmortem fusiform gyrus samples from 11 subjects with idiopathic autism and 13 controls and in valproic acid versus saline-exposed rat neocortex. Additionally, protein levels of brain-derived neurotrophic factor receptor (TrkB) isoforms and the postsynaptic organizing molecule PSD-95 were measured in autistic versus control subjects. RESULTS: Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus. Similarly, phosphorylated and total Akt, mTOR and 4E-BP1 and phosphorylated S6 protein were decreased in valproic acid- versus saline-exposed rats. However, no changes in 4E-BP1 or eIF4E were found in autistic brains. CONCLUSIONS: In contrast to some monogenic disorders with high rates of autism, our data demonstrate down-regulation of the Akt/mTOR pathway, specifically via p70S6K/eIF4B, in idiopathic autism. These findings suggest that disruption of this pathway in either direction is widespread in autism and can have adverse consequences for synaptic function. The use of valproic acid, a histone deacetylase inhibitor, in rats successfully modeled these changes, implicating an epigenetic mechanism in these pathway disruptions.
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These results further add to the literature supporting the idea that dysregulation of mTOR in either direction is likely important in ASD.
“Thus, these results further add to the literature supporting the idea that dysregulation of mTOR in either direction is likely important in ASD.104”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [104]
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- Authors
- Nicolini, C., Ahn, Y., Michalski, B., Rho, J. M., & Fahnestock, M.
- Affiliations
- McMaster University (CA)
- University of Calgary (CA)
- Corresponding author
- Fahnestock, Margaret
- Venue
- Acta Neuropathologica Communications
- Published
- 2015-01-20
- Volume
- 3
- Issue
- 1
- Pages
- 3-3
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC4307681
- OpenAlex
- W2118513080
- Cited by
- 109
- References
- 66
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 9 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 8 · 2019: 6 · 2018: 12 · 2017: 9 · 2016: 8 · 2015: 3
- FWCI
- 7.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Autism Speaks
- Alberta Children's Hospital Research Institute
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- idiopathic autism, mTOR signaling, Akt/mTOR signaling, valproic acid, animal models of autism, p70 S6 kinase, eIF4B, 4E-BP1, PSD-95, TrkB, phosphatidylinositol 3-kinase, synaptic plasticity, dendritic spines, histone deacetylase inhibition, epigenetics, fusiform gyrus, neocortex
- MeSH terms
- Disks Large Homolog 4 Protein, Adolescent, Adult, Animals, Anticonvulsants, Autistic Disorder, Child, Child, Preschool, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Male, Membrane Proteins, Middle Aged, Postmortem Changes, Pregnancy, Prenatal Exposure Delayed Effects, RNA, Messenger, Temporal Lobe, Valproic Acid, Signal Transduction, Intracellular Signaling Peptides and Proteins, Rats, Young Adult, TOR Serine-Threonine Kinases
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