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

Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.

Author information

1
Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
2
Department of Psychology, Columbia University Medical Center, New York, NY10032, USA.
3
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA; Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA.
4
Department of Psychiatry, Columbia University Medical Center, New York, NY10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
5
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA.
6
Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
8
Department of Neurology, Columbia University Medical Center, New York, NY10032, USA; Department of Psychiatry, Columbia University Medical Center, New York, NY10032, USA; Department of Pharmacology, Columbia University Medical Center, New York, NY10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA. Electronic address: ds43@columbia.edu.

Erratum in

  • Neuron. 2014 Sep 17;83(6):1482.

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.

PMID:
25155956
PMCID:
PMC4159743
DOI:
10.1016/j.neuron.2014.07.040
[Indexed for MEDLINE]
Free PMC Article

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