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

Marco Pagani,Michael V Lombardo,Ieva Miseviciute,Vinod Menon,Carola Canella,Noemi Barsotti,Stavros Trakoshis,Alberto Galbusera,Gustavo Deco,Kaustubh Supekar,Alessandro Gozzi,Alice Bertero,Alessia De Felice,Massimo Pasqualetti,Raffaella Tonini,Andrea Locarno,Laura Ulysse

doi:10.1038/s41467-021-26131-z

Abstract

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.

Highlights

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
insular cortex (Ins) keeping with the key involvement of mammalian target of rapamycin (mTOR)-pathway dysfunction in idiopathic ASD7,14,16, we further show that a similar connectivity fingerprint can be identified in resting-state fMRI (rsfMRI) scans of a subset of idiopathic ASD cases, and document that this hyperconnectivity pattern is enriched in genes that are dysregulated in the cortical transcriptome of ASD and interact with mTOR and Tsc[2] at the protein level
To probe whether ASD-relevant mTOR-dependent synaptic pathology is associated with a specific brain-wide signature of functional dysconnectivity, we carried out rsfMRI connectivity mapping in Tsc2+/− mutant mice

Summary

Introduction

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. Recent investigations of neuronal–microglia signaling in rodents support this notion, showing that developmental synaptic pruning critically governs the maturation of large-scale functional connectivity, biasing ASDrelevant sensory-motor and socio-communicative behavior[28] These observations point at a putative etiopathological link between translational control, synaptic pathophysiology, and brain-wide dysconnectivity, raising the question of whether dendritic spine abnormalities that characterize ASD (e.g., via mTOR hyperactivity). Related synaptic pathology and aberrant functional connectivity alterations in ASD We test this hypothesis by combining rsfMRI, viral tracing, in silico modeling, morphological and electrophysiological recordings in haploinsufficient tuberous sclerosis complex 2 mice (Tsc2+/−), a mouse line mechanistically reconstituting mTOR-dependent synaptic surplus observed in postmortem ASD investigations[7]. Our work establishes a mechanistic link between mTOR-related synaptic pathology and functional hyperconnectivity in ASD, and defines a multiscale cross-species platform enabling the decoding of ASD-specific pathophysiological traits from connectomics alterations in ASD populations

Methods

Results

Conclusion