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

• Published in: Nature communications 2021-10, Vol.12 (1), p.6084-6084, Article 6084
• Main Authors: Pagani, Marco, Barsotti, Noemi, Bertero, Alice, Trakoshis, Stavros, Ulysse, Laura, Locarno, Andrea, Miseviciute, Ieva, De Felice, Alessia, Canella, Carola, Supekar, Kaustubh, Galbusera, Alberto, Menon, Vinod, Tonini, Raffaella, Deco, Gustavo, Lombardo, Michael V., Pasqualetti, Massimo, Gozzi, Alessandro
• Format: Article
• Language: English
• Subjects: 38/39; 59/36; 631/378/1689/1373; 631/378/3920; 64/60; 9/74; Adolescent; Animals; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autism Spectrum Disorder - pathology; Autism Spectrum Disorder - physiopathology; Autopsy; Brain - diagnostic imaging; Brain - metabolism; Brain - pathology; Brain - physiopathology; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - metabolism; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Child; Children; Density; Electrophysiology; Female; Functional magnetic resonance imaging; Haploinsufficiency; Humanities and Social Sciences; Humans; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neostriatum; Neural networks; Pathology; Science; Science (multidisciplinary); Spine; Subgroups; Synapses; Synapses - genetics; Synapses - metabolism; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tuberous Sclerosis Complex 2 Protein - genetics; Tuberous Sclerosis Complex 2 Protein - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26131-z

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. Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.