biostudies-literaturePagani MNIMH NIH HHS6084https://www.ebi.ac.uk/biostudies/studies/S-EPMC8526836biostudies-literatureUnknown12(1)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 idiopathiNature communicationsmTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.PMC8526836R01 MH084164Tonini RBertero AUlysse LCanella CGalbusera ADe Felice ASupekar KLocarno AMenon VDeco GGozzi AMiseviciute IPasqualetti MLombardo MVBarsotti NPagani MTrakoshis SfalsemTOR-related synaptic pathology causes autism spectrum disorder-associated functional hyperconnectivity.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 idiopathi2021-01-01T00:00:00Z2021 Oct2026-03-27T16:15:23.889Z2025-04-05T22:20:20.819ZS-EPMC85268363466714910.1038/s41467-021-26131-z