Abstract
BackgroundThe 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.MethodsComponents 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.ResultsFull-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.ConclusionsIn 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.
Highlights
Autism is a neurodevelopmental disorder characterized by social communication and interaction impairments and restricted, repetitive patterns of behavior [1]
We investigated whether the Akt/ mTOR pathway, which is disrupted in monogenic disorders with high rates of autism, is altered in idiopathic autism
Contrary to disruptions seen in Fragile X syndrome, tuberous sclerosis, PTENrelated macrocephaly and neurofibromatosis type 1, developmental disorders with high rates of autism, we demonstrated decreased Akt/mTOR pathway in both patients with idiopathic autism and in Valproic acid (VPA)-exposed rats
Summary
Autism is a neurodevelopmental disorder characterized by social communication and interaction impairments and restricted, repetitive patterns of behavior [1]. Several studies point to the Akt/mTOR pathway, which regulates translation at dendritic spines [2,3], as a potential molecular substrate of autism. Autism-like phenotypes have been observed in Eif4ebp knockout and eIF4E-overexpressing mice [6], both downstream mTOR effectors regulating protein translation. These findings strengthen the hypothesis that disruptions in the mTOR pathway contribute to autism neuropathology, likely by negatively affecting spines, which are perturbed in subjects with autism [7]. 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
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