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dc.contributor.authorPagani, Marco
dc.contributor.authorBarsotti, Noemi
dc.contributor.authorBertero, Alice
dc.contributor.authorTrakoshis, Stavros
dc.contributor.authorUlysse, Laura
dc.contributor.authorLocarno, Andrea
dc.contributor.authorMiseviciute, Ieva
dc.contributor.authorDe Felice, Alessia
dc.contributor.authorCanella, Carola
dc.contributor.authorSupekar, Kaustubh
dc.contributor.authorGalbusera, Alberto
dc.contributor.authorMenon, Vinod
dc.contributor.authorTonini, Raffaella
dc.contributor.authorDeco, Gustavo
dc.contributor.authorLombardo, Michael V
dc.contributor.authorPasqualetti, Massimo
dc.contributor.authorGozzi, Alessandro
dc.date.accessioned2021-11-25T03:03:23Z
dc.date.available2021-11-25T03:03:23Z
dc.date.issued2021-10-19
dc.identifier.issn2041-1723
dc.identifier.otherPMC8526836
dc.identifier.other34667149
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331094
dc.description.abstractPostmortem 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.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 2041-1723
dc.sourcenlmid: 101528555
dc.titlemTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.
dc.typeArticle
dc.date.updated2021-11-25T03:03:23Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume12
dc.identifier.doi10.17863/CAM.78539
dc.identifier.doi10.17863/CAM.78539
dcterms.dateAccepted2021-09-17
rioxxterms.versionofrecord10.1038/s41467-021-26131-z
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidPagani, Marco [0000-0002-6052-6931]
dc.contributor.orcidGalbusera, Alberto [0000-0001-7213-0013]
dc.contributor.orcidTonini, Raffaella [0000-0003-1652-4709]
dc.contributor.orcidLombardo, Michael V [0000-0001-6780-8619]
dc.contributor.orcidPasqualetti, Massimo [0000-0002-0844-8139]
dc.contributor.orcidGozzi, Alessandro [0000-0002-5731-4137]
dc.identifier.eissn2041-1723
cam.issuedOnline2021-10-19


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International