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.

Tang G¹, Gudsnuk K², Kuo SH¹, Cotrina ML³, Rosoklija G⁴, Sosunov A⁵, Sonders MS¹, Kanter E¹, Castagna C¹, Yamamoto A¹, Yue Z⁶, Arancio O⁵, Peterson BS⁴, Champagne F², Dwork AJ⁷, Goldman J⁵, Sulzer D⁸.

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.