A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivity in autism

Abstract

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.SignificanceAberrant 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.

Unique spatiotemporal fMRI dynamics in the awake mouse brain

“…1,2 The use of these methods in the mouse has highlighted encouraging cross-species correspondences in the organization of functional networks, 2,3 offering novel opportunities to mechanistically probe the neural basis of brain-wide fMRI coupling and its breakdown in brain disorders. [4][5][6] To ensure immobilization of animals during image acquisition and prevent motion-related artifacts, the vast majority of mouse rsfMRI studies to date have been carried out using light anesthesia. 7,8 While the employed protocols have been shown to preserve the functional 7,9 and dynamic architecture 10 of rsfMRI networks in this species, anesthetic agents can alter hemodynamic and neurovascular coupling, 11,12 or generate unwanted genetic or pharmacological interactions 13 that can confound the mechanistic interpretation of rsfMRI signals.…”

Somatosensory processing deficits and altered cortico-hippocampal connectivity inShank3b−/−mice

“…All functional connectivity analyses reported here were carried out on the rsfMRI scans acquired for the Pagani et al 2019 study (25). The protocol for animal preparation employed was detailed in our previous studies (25, 48–50). Briefly, animals were anaesthetized with isoflurane (5% induction), intubated and artificially ventilated (2% maintenance).…”

Paradoxical fMRI overconnectivity upon chemogenetic silencing of the 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 7,15,16 . Moreover, rsfMRI network topography can dynamically reconfigure in response to local perturbations 17 or pathological processes 18 . 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 19,20 .…”