Loss of mTOR-dependent Macroautophagy Causes Autistic-Like Synaptic Pruning Deficits

Neuron. 2014 Sep 3;83(5):1131-43. doi: 10.1016/j.neuron.2014.07.040. Epub 2014 Aug 21.

Abstract

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age Factors
  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / pathology*
  • Autophagy / drug effects
  • Autophagy / physiology*
  • Child
  • Child, Preschool
  • Dendritic Spines / genetics*
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Female
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / pathology*
  • Sirolimus / pharmacology
  • Synapses / drug effects
  • Synapses / pathology*
  • TOR Serine-Threonine Kinases / metabolism*
  • Temporal Lobe / pathology
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Young Adult

Substances

  • Immunosuppressive Agents
  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus