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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 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.
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Fig7: 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.

Mentions: Western blotting revealed a statistically significant decrease in both total and phosphorylated Akt (**p = 0.002, Figure 7A; **p = 0.004, Figure 8A; 2-tailed t tests), mTOR (***p < 0.0001, Figure 7B; ***p < 0.0001, Figure 8B; 2-tailed t tests) and 4E-BP1 (***p < 0.0001, Figure 7D; ***p < 0.0001, Figure 8D; 2-tailed t tests) in VPA-exposed rats compared to saline-exposed controls. However, only phosphorylated (***p < 0.0001, Figure 8C; 2-tailed t test) but not total (p = 0.6, Figure 7C; 2-tailed t test) S6 protein expression was significantly reduced in VPA- versus saline-exposed rats.Figure 7


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 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.
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Fig7: 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.
Mentions: Western blotting revealed a statistically significant decrease in both total and phosphorylated Akt (**p = 0.002, Figure 7A; **p = 0.004, Figure 8A; 2-tailed t tests), mTOR (***p < 0.0001, Figure 7B; ***p < 0.0001, Figure 8B; 2-tailed t tests) and 4E-BP1 (***p < 0.0001, Figure 7D; ***p < 0.0001, Figure 8D; 2-tailed t tests) in VPA-exposed rats compared to saline-exposed controls. However, only phosphorylated (***p < 0.0001, Figure 8C; 2-tailed t test) but not total (p = 0.6, Figure 7C; 2-tailed t test) S6 protein expression was significantly reduced in VPA- versus saline-exposed rats.Figure 7

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