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

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.

Functional Connectivity of the Brain Across Rodents and Humans

“…Moreover, in humans, the aberrant connections in the DMN or/and in its interplay with other networks have been found to constitute the "connectopathy" in many neurologic conditions such as Attention-deficit/hyperactivity disorder (ADHD) (Uddin et al, 2008), Autism spectrum disorder (ASD) (Uddin et al, 2019), Alzheimer's disease and aging (Toga and Thompson, 2014). Notably, a similar "connectopathy" involving aberrant rodent's DMN was also discovered in recent studies using transgenic mice for Autism Spectrum Disorder (Pagani et al, 2021) and Alzheimer's disease (Adhikari et al, 2021). Despite these similarities across rodents and humans, discrepancies remain.…”

“…A great example of this is seen in studies of Autism Spectral Disorder (ASD) where genetic alterations play a large role in the development of the disease ( Sandin et al, 2017 ). In such efforts, the use of ASD rodent models containing gene-specific mutations has proven incredibly useful in the study of underlying dysfunctions in brain connectomes and functional connectivity ( Pagani et al, 2021 ; Zerbi et al, 2021 ). However, choosing a rodent model must be done carefully as many variables, such as the difference in brain structure and function between rodents and humans as well as the type of rodent used ( Jonckers et al, 2011 ; Ellenbroek and Youn, 2016 ), act as contributing factors to the efficacy of the model.…”

Increased fMRI connectivity upon chemogenetic inhibition of the mouse prefrontal cortex

“…This notion is epitomized by the observation of intact rsfMRI coupling among brain regions not directly structurally connected as in the case of acallosal humans, primates, and rodents 7 , 14 , 15 . Moreover, rsfMRI network topography can dynamically reconfigure in response to local perturbations 16 or pathological processes 17 . In keeping with this, neurological disorders such as Parkinson’s disease, stroke, and Alzheimer’s disease have been often found to be associated with unexpectedly increased interareal rsfMRI connectivity despite the loss of cortical function characterizing these conditions 18 , 19 .…”

Whole-brain comparison of rodent and human brains using spatial transcriptomics

“…In the preclinical setting, mouse models are utilized with the intention of better under-standing human neuropathology. For instance, in the context of autism spectrum disorders, a plethora of studies using mouse models have reported on the neurobiological and neuroanatomical phenotypes that arise from mutations at specific genetic loci (31–33) . It is common for researchers involved in translational neuroscience to rely on findings of this kind to make inferences about the human disorder.…”