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Cited by 109Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchPI3K/AKT/mTOR signaling in cancer

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Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid

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Nicolini, Chiara, Ahn, Younghee, Michalski, Bernadeta, Rho, Jong M, Fahnestock, Margaret·2015·Acta Neuropathologica Communications
DOI 10.1186/s40478-015-0184-4PMC PMC4307681
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Abstract

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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Figure 1 Quantification of (A) PI3K p85 and (C) Akt protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. *p = 0.03 for PI3K p85 and Akt, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B) and (D) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 35 μg for PI3K p85 and 15 μg for Akt of total protein from each autism and control sample were loaded.
Figure 1 Quantification of (A) PI3K p85 and (C) Akt protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. *p = 0.03 for PI3K p85 and Akt, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B) and (D) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 35 μg for PI3K p85 and 15 μg for Akt of total protein from each autism and control sample were loaded.CC BY · PubMed Central
Figure 2 Quantification by Western blotting and representative Western blots of (A) total mTOR and (B) phospho-mTOR protein expression in autism versus control fusiform gyrus samples. Each sample was normalized to its β-actin. **p = 0.003 for mTOR, ***p = 0.0003 for phospho-mTOR, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. 35 μg for mTOR and 50 μg for phospho-mTOR of total protein from each autism (A) and control (C) sample were loaded.
Figure 2 Quantification by Western blotting and representative Western blots of (A) total mTOR and (B) phospho-mTOR protein expression in autism versus control fusiform gyrus samples. Each sample was normalized to its β-actin. **p = 0.003 for mTOR, ***p = 0.0003 for phospho-mTOR, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. 35 μg for mTOR and 50 μg for phospho-mTOR of total protein from each autism (A) and control (C) sample were loaded.CC BY · PubMed Central
Figure 3 Quantification of (A) p70S6K, (C) eIF4B, (E) 4E-BP1 and (G) eIF4E protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. **p = 0.002 for p70S6K, *p = 0.02 for eIF4B, p = 0.6 for 4E-BP1 and p = 0.4 for eIF4E, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B), (D), (F) and (H) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 35 μg for p70S6K, eIF4B and 4E-BP1 and 20 μg for eIF4E of total protein from each autism and control sample were loaded.
Figure 3 Quantification of (A) p70S6K, (C) eIF4B, (E) 4E-BP1 and (G) eIF4E protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. **p = 0.002 for p70S6K, *p = 0.02 for eIF4B, p = 0.6 for 4E-BP1 and p = 0.4 for eIF4E, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B), (D), (F) and (H) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 35 μg for p70S6K, eIF4B and 4E-BP1 and 20 μg for eIF4E of total protein from each autism and control sample were loaded.CC BY · PubMed Central
Figure 4 Quantification of (A) PSD-95 protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. *p = 0.02, 2-tailed t test. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from three independent Western blots per sample was used for statistical analysis. (B) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 20 μg of total protein from each autism and control sample were loaded.
Figure 4 Quantification of (A) PSD-95 protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. *p = 0.02, 2-tailed t test. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from three independent Western blots per sample was used for statistical analysis. (B) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 20 μg of total protein from each autism and control sample were loaded.CC BY · PubMed Central
Figure 5 Quantification of (A) full-length (FL)/truncated and (B) truncated/full-length (FL) TrkB isoform protein ratios in fusiform gyrus of autism and control samples. **p = 0.002 and **p = 0.009, respectively, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. (C) Quantification of full-length (FL) TrkB and (E) truncated TrkB isoform protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. **p = 0.003 for TrkB-FL and p = 0.09 for truncated TrkB isoforms, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (D) and (F) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. Lanes 2 to 5: standard curve consisting of different amounts of total protein from a single normal human cortex sample. Lanes 6 to 13: 35 μg of total protein from each autism and control sample.
Figure 5 Quantification of (A) full-length (FL)/truncated and (B) truncated/full-length (FL) TrkB isoform protein ratios in fusiform gyrus of autism and control samples. **p = 0.002 and **p = 0.009, respectively, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. (C) Quantification of full-length (FL) TrkB and (E) truncated TrkB isoform protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. **p = 0.003 for TrkB-FL and p = 0.09 for truncated TrkB isoforms, 2-tailed t tests. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (D) and (F) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. Lanes 2 to 5: standard curve consisting of different amounts of total protein from a single normal human cortex sample. Lanes 6 to 13: 35 μg of total protein from each autism and control sample.CC BY · PubMed Central
Figure 6 Quantification of (A) Beta-III Tubulin and (C) GFAP protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. As reported by other studies [38,39], four bands ranging from 38 kDa to 50 kDa were detected for GFAP in all samples and quantified together. p = 0.5 for βIII-tubulin, p = 0.4 for GFAP, 2-tailed t test. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B) and (D) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 20 μg for Beta-III Tubulin and 5 μg for GFAP of total protein from each autism and control sample were loaded.
Figure 6 Quantification of (A) Beta-III Tubulin and (C) GFAP protein expression in fusiform gyrus of autism and control samples by Western blotting. Each sample was normalized to its β-actin. As reported by other studies [38,39], four bands ranging from 38 kDa to 50 kDa were detected for GFAP in all samples and quantified together. p = 0.5 for βIII-tubulin, p = 0.4 for GFAP, 2-tailed t test. Bars indicate mean ± SE. Autism, n = 11; control, n = 13. The mean from two independent Western blots per sample was used for statistical analysis. (B) and (D) Representative Western blots of fusiform gyrus showing autism (A) and control (C) cases. 20 μg for Beta-III Tubulin and 5 μg for GFAP of total protein from each autism and control sample were loaded.CC BY · PubMed Central
Figure 7 Quantification by Western blotting and representative Western blots of total (A) Akt, (B) mTOR, (C) S6 and (D) 4E-BP1 protein expression in VPA- versus saline (SAL)-exposed rat lateral temporal neocortices. Each sample was normalized to its β-actin, and VPA-exposed values were expressed relative to SAL-exposed. All p-values were calculated by 2-tailed t test. Akt: **p = 0.002, SAL, n = 5; VPA, n = 5; mTOR: ***p < 0.0001, SAL, n = 8; VPA, n = 8; S6: p = 0.5, SAL, n = 8; VPA, n = 8; 4E-BP1: ***p < 0.0001, SAL, n = 6; VPA, n = 6. Bars indicate mean ± SE. The mean from three independent Western blots per sample was used for statistical analysis.
Figure 7 Quantification by Western blotting and representative Western blots of total (A) Akt, (B) mTOR, (C) S6 and (D) 4E-BP1 protein expression in VPA- versus saline (SAL)-exposed rat lateral temporal neocortices. Each sample was normalized to its β-actin, and VPA-exposed values were expressed relative to SAL-exposed. All p-values were calculated by 2-tailed t test. Akt: **p = 0.002, SAL, n = 5; VPA, n = 5; mTOR: ***p < 0.0001, SAL, n = 8; VPA, n = 8; S6: p = 0.5, SAL, n = 8; VPA, n = 8; 4E-BP1: ***p < 0.0001, SAL, n = 6; VPA, n = 6. Bars indicate mean ± SE. The mean from three independent Western blots per sample was used for statistical analysis.CC BY · PubMed Central
Figure 8 Quantification by Western blotting and representative Western blots of phosphorylated (A) Akt, (B) mTOR, (C) S6 and (D) 4E-BP1 protein expression in VPA- versus saline (SAL)-exposed rat lateral temporal neocortices. Each sample was normalized to its β-actin, and VPA-exposed values were expressed relative to SAL-exposed. All p-values were calculated by 2-tailed t test. Phospho-Akt: **p = 0.004, SAL, n = 4; VPA, n = 4; phospho-mTOR: ***p < 0.0001, SAL, n = 8; VPA, n = 8; phospho-S6: ***p < 0.0001, SAL, n = 8; VPA, n = 8; phospho-4E-BP1: ***p < 0.0001, SAL, n = 6; VPA, n = 6. Bars indicate mean ± SE. The mean from three independent Western blots per sample was used for statistical analysis.
Figure 8 Quantification by Western blotting and representative Western blots of phosphorylated (A) Akt, (B) mTOR, (C) S6 and (D) 4E-BP1 protein expression in VPA- versus saline (SAL)-exposed rat lateral temporal neocortices. Each sample was normalized to its β-actin, and VPA-exposed values were expressed relative to SAL-exposed. All p-values were calculated by 2-tailed t test. Phospho-Akt: **p = 0.004, SAL, n = 4; VPA, n = 4; phospho-mTOR: ***p < 0.0001, SAL, n = 8; VPA, n = 8; phospho-S6: ***p < 0.0001, SAL, n = 8; VPA, n = 8; phospho-4E-BP1: ***p < 0.0001, SAL, n = 6; VPA, n = 6. Bars indicate mean ± SE. The mean from three independent Western blots per sample was used for statistical analysis.CC BY · PubMed Central

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  1. Ahn Y, Narous M, Tobias R, Hu B, Rho JM (2012) Alterations in social behavior and mTOR signaling in the valproic acid-induced model of autism spectrum disorder, Program No. 861.21. 2012 Neuroscience Meeting Planner. Society for Neuroscience, New Orleans, LA, Online

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Metadata

Authors
Nicolini, C., Ahn, Y., Michalski, B., Rho, J. M., & Fahnestock, M.
Affiliations
  • McMaster University (CA)
  • University of Calgary (CA)
Corresponding author
Fahnestock, Margaret
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2015-01-20
Volume
3
Issue
1
Pages
3-3
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-015-0184-4
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
Licence
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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