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

Acta Neuropathol Commun. 2015 Jan 20:3:3. doi: 10.1186/s40478-015-0184-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Anticonvulsants / toxicity*
  • Autistic Disorder / pathology*
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Female
  • Gene Expression Regulation / drug effects*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Middle Aged
  • Postmortem Changes
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / pathology
  • Prenatal Exposure Delayed Effects / physiopathology
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • TOR Serine-Threonine Kinases / metabolism*
  • Temporal Lobe / metabolism*
  • Valproic Acid / toxicity*
  • Young Adult

Substances

  • Anticonvulsants
  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • RNA, Messenger
  • Valproic Acid
  • MTOR protein, human
  • TOR Serine-Threonine Kinases