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

• Published in: Acta neuropathologica communications Vol. 3; no. 1; p. 3
• Main Authors: Nicolini, Chiara, Ahn, Younghee, Michalski, Bernadeta, Rho, Jong M, Fahnestock, Margaret
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.01.2015; BioMed Central
• Subjects: Adolescent; Adult; Animals; Anticonvulsants - toxicity; Autism; Autistic Disorder - pathology; Cellular signal transduction; Child; Child, Preschool; Disease Models, Animal; Disks Large Homolog 4 Protein; Divalproex; Drug therapy; Epigenetic inheritance; Female; Gene Expression Regulation - drug effects; Genetic aspects; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Male; Membrane Proteins - metabolism; Middle Aged; Patient outcomes; Postmortem Changes; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - pathology; Prenatal Exposure Delayed Effects - physiopathology; Protein biosynthesis; Rats; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Temporal Lobe - metabolism; TOR Serine-Threonine Kinases - metabolism; Valproic acid; Valproic Acid - toxicity; Young Adult
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-015-0184-4

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. 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. 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. 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.