4.8 Article

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

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26131-z

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资金

  1. Simons Foundation [SFARI 400101, SFARI 308939]
  2. Brain and Behavior Foundation 2017 (NARSAD-National Alliance for Research on Schizophrenia and Depression)
  3. European Research Council (ERC-DISCONN) [GA802371]
  4. European Union [845065]
  5. European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [755816]
  6. NIH [MH084164]
  7. Spanish Ministry of Science, Innovation and Universities (MCIU) [PID2019-105772GB-I00]
  8. State Research Agency (AEI) [PID2019-105772GB-I00]
  9. European Regional Development Funds (FEDER) [PID2019-105772GB-I00]
  10. HBP SGA3 Human Brain Project Specific Grant Agreement 3 - EU H2020 FET Flagship program [945539]
  11. SGR Research Support Group support - Catalan Agency for Management of University and Research Grants (AGAUR) [2017 SGR 1545]
  12. BRAIN-CONNECTS: Brain Connectivity during Stroke Recovery and Rehabilitation - Fundacio La Marato de TV3 2017 [201725.33]
  13. Marie Curie Actions (MSCA) [845065] Funding Source: Marie Curie Actions (MSCA)

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Research indicates that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and hyperconnectivity, which is also found in children with idiopathic ASD. These findings link mTOR-related synaptic pathology to large-scale network aberrations in autism, providing a new perspective on the mechanistic understanding of the disorder.
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. 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.

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