1. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits
- Author
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David Sulzer, Sheng-Han Kuo, Gorazd Rosoklija, Mark S. Sonders, Ai Yamamoto, Guomei Tang, Zhenyu Yue, James E. Goldman, Andrew J. Dwork, Bradley S. Peterson, Frances A. Champagne, Ellen Kanter, Kathryn Gudsnuk, Alexander A. Sosunov, Ottavio Arancio, Marisa L. Cotrina, and Candace Castagna
- Subjects
Male ,Dendritic spine ,Synaptic pruning ,Mice ,0302 clinical medicine ,Child ,Neurons ,0303 health sciences ,TOR Serine-Threonine Kinases ,General Neuroscience ,Age Factors ,musculoskeletal system ,Temporal Lobe ,medicine.anatomical_structure ,Child, Preschool ,Excitatory postsynaptic potential ,Female ,Immunosuppressive Agents ,medicine.drug ,musculoskeletal diseases ,Adolescent ,Dendritic Spines ,Neuroscience(all) ,Mice, Transgenic ,Biology ,behavioral disciplines and activities ,Article ,Young Adult ,03 medical and health sciences ,Tuberous Sclerosis Complex 2 Protein ,mental disorders ,medicine ,Autophagy ,Animals ,Humans ,Autistic Disorder ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Sirolimus ,Tumor Suppressor Proteins ,medicine.disease ,Disease Models, Animal ,nervous system ,Synapses ,Exploratory Behavior ,Autism ,TSC2 ,Neuroscience ,030217 neurology & neurosurgery - Abstract
SummaryDevelopmental 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 Atg7CKO neuronal autophagy-deficient mice or Tsc2+/−:Atg7CKO 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.
- Published
- 2014
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