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

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.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