title: Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.
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.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Guomei
authors.initials: G
authors.lastname: Tang
authors.affiliation: Department of Psychology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Gudsnuk
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: 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.
authors.forename: Marisa L
authors.initials: ML
authors.lastname: Cotrina
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
authors.forename: Gorazd
authors.initials: G
authors.lastname: Rosoklija
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sosunov
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sonders
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Kanter
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Candace
authors.initials: C
authors.lastname: Castagna
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Ai
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Departments of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Peterson
authors.affiliation: Department of Psychology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Champagne
authors.affiliation: 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.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dwork
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY10032, USA.
authors.forename: James
authors.initials: J
authors.lastname: Goldman
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Sulzer
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D049229:Dendritic Spines / Q000235:genetics*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D020123:Sirolimus / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013702:Temporal Lobe / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus