mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity

Autor: Ieva Miseviciute, Alice Bertero, Kaustubh Supekar, Stavros Trakoshis, Massimo Pasqualetti, Gustavo Deco, Alberto Galbusera, Raffaella Tonini, Alessandro Gozzi, Marco Pagani, Carola Canella, Michael V. Lombardo, Alessia De Felice, Andrea Locarno, Laura Ulysse, Vinod Menon, Noemi Barsotti
Přispěvatelé: Pagani, Marco [0000-0002-6052-6931], Galbusera, Alberto [0000-0001-7213-0013], Tonini, Raffaella [0000-0003-1652-4709], Lombardo, Michael V. [0000-0001-6780-8619], Pasqualetti, Massimo [0000-0002-0844-8139], Gozzi, Alessandro [0000-0002-5731-4137], Apollo - University of Cambridge Repository, Lombardo, Michael V [0000-0001-6780-8619]
Rok vydání: 2021
Předmět:
Male
Postmortem studies
Autism Spectrum Disorder
Synaptic pruning
General Physics and Astronomy
Haploinsufficiency
spectrum
Mice
autism
connectivity
inhibition
pathology
Child
health care economics and organizations
Cerebral Cortex
Mice
Knockout
Multidisciplinary
631/378/3920
TOR Serine-Threonine Kinases
9/74
article
food and beverages
Brain
Hyperconnectivity
Autism spectrum disorders
Magnetic Resonance Imaging
medicine.anatomical_structure
Autism spectrum disorder
59/36
Synaptopathy
Female
64/60
38/39
Adolescent
Science
631/378/1689/1373
Biology
Neural circuits
behavioral disciplines and activities
General Biochemistry
Genetics and Molecular Biology
Tuberous Sclerosis Complex 2 Protein
mental disorders
medicine
Animals
Humans
PI3K/AKT/mTOR pathway
General Chemistry
medicine.disease
Mice
Inbred C57BL
Synapses
Autism
Neuroscience
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021)
ORCID
Microsoft Academic Graph
PubMed Central
DOAJ-Articles
Datacite
Apollo
essn: 2041-1723
Nature Communications
nlmid: 101528555
ISSN: 2041-1723
Popis: 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.
Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.
Databáze: OpenAIRE
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