mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.
Adolescent
Animals
Autism Spectrum Disorder
/ genetics
Brain
/ diagnostic imaging
Cerebral Cortex
/ diagnostic imaging
Child
Female
Haploinsufficiency
Humans
Magnetic Resonance Imaging
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Synapses
/ genetics
TOR Serine-Threonine Kinases
/ genetics
Tuberous Sclerosis Complex 2 Protein
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 10 2021
19 10 2021
Historique:
received:
30
10
2020
accepted:
17
09
2021
entrez:
20
10
2021
pubmed:
21
10
2021
medline:
1
12
2021
Statut:
epublish
Résumé
Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.
Identifiants
pubmed: 34667149
doi: 10.1038/s41467-021-26131-z
pii: 10.1038/s41467-021-26131-z
pmc: PMC8526836
doi:
Substances chimiques
Tsc2 protein, mouse
0
Tuberous Sclerosis Complex 2 Protein
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6084Informations de copyright
© 2021. The Author(s).
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