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

Nicolini C, Ahn Y, Michalski B, Rho JM, Fahnestock M - Acta Neuropathol Commun (2015)

Bottom Line: The molecular mechanisms underlying autistic behaviors remain to be elucidated.Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus.However, no changes in 4E-BP1 or eIF4E were found in autistic brains.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry & Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton L8S 4K1, ON, Canada. fahnest@mcmaster.ca.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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Fig1: 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.

Mentions: Akt/mTOR pathway protein expression levels were examined in the fusiform gyrus of subjects with idiopathic autism versus control subjects. Fusiform gyrus is an area of the brain implicated in face discrimination and perception difficulties of autistic subjects [29,32]. Western blotting revealed a statistically significant decrease in PI3K p85 and Akt (*p = 0.03, Figure 1A,B; *p = 0.03, Figure 1C,D; 2-tailed t tests) protein in the fusiform gyrus of autistic subjects relative to controls.Figure 1


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

Nicolini C, Ahn Y, Michalski B, Rho JM, Fahnestock M - Acta Neuropathol Commun (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4307681&req=5

Fig1: 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.
Mentions: Akt/mTOR pathway protein expression levels were examined in the fusiform gyrus of subjects with idiopathic autism versus control subjects. Fusiform gyrus is an area of the brain implicated in face discrimination and perception difficulties of autistic subjects [29,32]. Western blotting revealed a statistically significant decrease in PI3K p85 and Akt (*p = 0.03, Figure 1A,B; *p = 0.03, Figure 1C,D; 2-tailed t tests) protein in the fusiform gyrus of autistic subjects relative to controls.Figure 1

Bottom Line: The molecular mechanisms underlying autistic behaviors remain to be elucidated.Full-length TrkB, PI3K, Akt, phosphorylated and total mTOR, p70S6 kinase, eIF4B and PSD-95 were reduced in autistic versus control fusiform gyrus.However, no changes in 4E-BP1 or eIF4E were found in autistic brains.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry & Behavioural Neurosciences, McMaster University, 1280 Main Street West, Hamilton L8S 4K1, ON, Canada. fahnest@mcmaster.ca.

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.

No MeSH data available.


Related in: MedlinePlus