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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.accessioned2021-10-19T15:42:53Z
dc.date.available2021-10-19T15:42:53Z
dc.date.issued2021-10-19
dc.date.submitted2020-10-30
dc.identifier.others41467-021-26131-z
dc.identifier.other26131
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329613
dc.description.abstractAbstract: 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.
dc.languageen
dc.publisherNature Publishing Group UK
dc.subjectArticle
dc.subject/631/378/1689/1373
dc.subject/631/378/3920
dc.subject/64/60
dc.subject/59/36
dc.subject/38/39
dc.subject/9/74
dc.subjectarticle
dc.titlemTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity
dc.typeArticle
dc.date.updated2021-10-19T15:42:52Z
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.volume12
dc.identifier.doi10.17863/CAM.77062
dcterms.dateAccepted2021-09-17
rioxxterms.versionofrecord10.1038/s41467-021-26131-z
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://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


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