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 ...
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.
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