RT Journal Article
SR Electronic
T1 A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivity in autism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.10.07.329292
DO 10.1101/2020.10.07.329292
A1 Marco Pagani
A1 Alice Bertero
A1 Stavros Trakoshis
A1 Laura Ulysse
A1 Andrea Locarno
A1 Ieva Miseviciute
A1 Alessia De Felice
A1 Carola Canella
A1 Kausthub Supekar
A1 Alberto Galbusera
A1 Vinod Menon
A1 Raffaella Tonini
A1 Gustavo Deco
A1 Michael V. Lombardo
A1 Massimo Pasqualetti
A1 Alessandro Gozzi
YR 2020
UL http://biorxiv.org/content/early/2020/10/08/2020.10.07.329292.abstract
AB Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism, with a putative link to aberrant mTOR-dependent synaptic pruning. Autism 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 cause aberrant functional connectivity in autism. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with autism-like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic autism exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for autism-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.Significance Aberrant brain functional connectivity is a hallmark of autism, but the neural basis of this phenomenon remains unclear. We show that a mouse line recapitulating mTOR-dependent synaptic pruning deficits observed in postmortem autistic brains exhibits widespread functional hyperconnectivity. Importantly, pharmacological normalization of mTOR signalling completely rescues synaptic, behavioral and functional connectivity deficits. We also show that a similar connectivity fingerprint can be isolated in human fMRI scans of people with autism, where it is linked to over-expression of mTOR-related genes. Our results reveal a unifying multi-scale translational framework that mechanistically links aberrations in synaptic pruning with functional hyperconnectivity in autism.Competing Interest StatementThe authors have declared no competing interest.