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

Marco Pagani, Noemi Barsotti, Alice Bertero, Stavros Trakoshis, Laura Ulysse, Andrea Locarno, Ieva Miseviciute, Alessia De Felice, Carola Canella, Kaustubh Supekar, Alberto Galbusera, Vinod Menon, Raffaella Tonini, Gustavo Deco, Michael V. Lombardo, Massimo Pasqualetti and Alessandro Gozzi ()
Additional contact information
Marco Pagani: Center for Neuroscience and Cognitive Systems @ University of Trento
Noemi Barsotti: University of Pisa
Alice Bertero: Center for Neuroscience and Cognitive Systems @ University of Trento
Stavros Trakoshis: University of Cyprus
Laura Ulysse: Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies
Andrea Locarno: Istituto Italiano di Tecnologia
Ieva Miseviciute: Istituto Italiano di Tecnologia
Alessia De Felice: Center for Neuroscience and Cognitive Systems @ University of Trento
Carola Canella: Center for Neuroscience and Cognitive Systems @ University of Trento
Kaustubh Supekar: Stanford University
Alberto Galbusera: Center for Neuroscience and Cognitive Systems @ University of Trento
Vinod Menon: Stanford University
Raffaella Tonini: Istituto Italiano di Tecnologia
Gustavo Deco: Center for Brain and Cognition, Computational Neuroscience Group, Department of Information and Communication Technologies
Michael V. Lombardo: Center for Neuroscience and Cognitive Systems @ University of Trento
Massimo Pasqualetti: Center for Neuroscience and Cognitive Systems @ University of Trento
Alessandro Gozzi: Center for Neuroscience and Cognitive Systems @ University of Trento

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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 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.

Date: 2021
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DOI: 10.1038/s41467-021-26131-z

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