mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.
De Felice, Alessia
Springer Science and Business Media LLC
MetadataShow full item record
Pagani, M., Barsotti, N., Bertero, A., Trakoshis, S., Ulysse, L., Locarno, A., Miseviciute, I., et al. (2021). mTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.. Nat Commun, 12 (1) https://doi.org/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.
Adolescent, Animals, Autism Spectrum Disorder, Brain, Cerebral Cortex, Child, Female, Haploinsufficiency, Humans, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Synapses, TOR Serine-Threonine Kinases, Tuberous Sclerosis Complex 2 Protein
External DOI: https://doi.org/10.1038/s41467-021-26131-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331094
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
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