Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.
Neuron
; 83(5): 1131-43, 2014 Sep 03.
Article
em En
| MEDLINE
| ID: mdl-25155956
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transtorno Autístico
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Autofagia
/
Sinapses
/
Espinhas Dendríticas
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Serina-Treonina Quinases TOR
/
Neurônios
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Animals
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Child
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Child, preschool
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article