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

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Pagani, Marco
• dc.contributor.author Barsotti, Noemi
• dc.contributor.author Bertero, Alice
• dc.contributor.author Trakoshis, Stavros
• dc.contributor.author Ulysse, Laura
• dc.contributor.author Locarno, Andrea
• dc.contributor.author Miseviciute, Ieva
• dc.contributor.author De Felice, Alessia
• dc.contributor.author Canella, Carola
• dc.contributor.author Supekar, Kaustubh
• dc.contributor.author Galbusera, Alberto
• dc.contributor.author Menon, Vinod
• dc.contributor.author Tonini, Raffaella
• dc.contributor.author Deco, Gustavo
• dc.contributor.author Lombardo, Michael V.
• dc.contributor.author Pasqualetti, Massimo
• dc.contributor.author Gozzi, Alessandro
• dc.date.accessioned 2022-07-04T06:15:26Z
• dc.date.available 2022-07-04T06:15:26Z
• dc.date.issued 2021
• dc.description.abstract 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 mTORdependent 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.description.sponsorship This work was supported by Simons Foundation Grants (SFARI 400101) to A. Gozzi. A. Gozzi was also supported by Brain and Behavior Foundation 2017 (NARSAD—National Alliance for Research on Schizophrenia and Depression) and the European Research Council (ERC—DISCONN, GA802371. M. Pagani was supported by the European Union’s Horizon 2020 research and innovation programme under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 845065 (Marie Sklodowska-Curie Global Fellowship - CANSAS). M.V. Lombardo was funded during this period of work by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No 755816. V.M and K.S. were supported by grants from the Simons Foundation (SFARI 308939) and the NIH (MH084164). G. Deco was supported by AWAKENING Using whole-brain models perturbational approaches for predicting external stimulation to force transitions between different brain states (ref. PID2019-105772GB-I00, AEI FEDER EU) funded by the Spanish Ministry of Science, Innovation and Universities (MCIU), State Research Agency (AEI) and European Regional Development Funds (FEDER), HBP SGA3 Human Brain Project Specific Grant Agreement 3 (Grant Agreement No. 945539), funded by the EU H2020 FET Flagship program, and SGR Research Support Group support (ref. 2017 SGR 1545), funded by the Catalan Agency for Management of University and Research Grants (AGAUR). L. Ulysse was supported by BRAIN-CONNECTS: Brain Connectivity during Stroke Recovery and Rehabilitation (Id. 201725.33), Funded by the Fundacio La Marato de TV3 2017.
• dc.format.mimetype application/pdf
• dc.identifier.citation Pagani M, Barsotti N, Bertero A, Trakoshis S, Ulysse L, Locarno A, Miseviciute I, De Felice A, Canella C, Supekar K, Galbusera A, Menon V, Tonini R, Deco G, Lombardo MV, Pasqualetti M, Gozzi A. mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity. Nat Commun. 2021;12:6084. DOI: 10.1038/s41467-021-26131-z
• dc.identifier.doi http://doi.org/10.1038/s41467-021-26131-z
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/53659
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2021;12:6084.
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/945539
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-105772GB-I00
• dc.rights © The Author(s) 2021 This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Autism spectrum disorders
• dc.subject.keyword Neural circuits
• dc.title mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion