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

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorder (ASD) is linked to increased excitatory synapses and abnormal brain connectivity.
• Aberrant mTOR signaling and synaptic pruning are implicated in ASD pathogenesis.

Purpose of the Study:

• To investigate the causal link between mTOR-dependent synaptic pathology and aberrant functional connectivity in autism spectrum disorder.
• To identify potential therapeutic targets and subtypes of autism.

Main Methods:

• Resting-state fMRI (rsfMRI), electrophysiology, and in silico modeling in Tsc2 haploinsufficient mice.
• Pharmacological inhibition of mTOR.
• Analysis of cortical-striatal connectivity in children with idiopathic ASD.
• Transcriptomic analysis of ASD-dysregulated genes interacting with mTOR/Tsc2.

Main Results:

• Increased spine density in mice with Tsc2 deficiency was associated with ASD-like behaviors and cortico-striatal hyperconnectivity.
• mTOR inhibition rescued these deficits in mice.
• Children with idiopathic ASD showed similar cortico-striatal hyperconnectivity.
• This connectivity pattern was enriched for genes interacting with mTOR or Tsc2, defining a potential autism subtype.

Conclusions:

• mTOR-related synaptic pathology causally contributes to large-scale network abnormalities in autism spectrum disorder.
• This provides a multi-scale framework linking synaptic dysfunction to network hyperconnectivity.
• Identified a molecular signature that may define a segregable autism subtype.