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

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

Fig2: 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.

Mentions: Total and phosphorylated mTOR were also decreased in autism versus control brain (**p = 0.003, Figure 2A; ***p = 0.0003, Figure 2B; 2-tailed t tests).Figure 2


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

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

Fig2: 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.
Mentions: Total and phosphorylated mTOR were also decreased in autism versus control brain (**p = 0.003, Figure 2A; ***p = 0.0003, Figure 2B; 2-tailed t tests).Figure 2

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