Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

V Zerbi,Y Bozzi,F Helmchen,M Fagiolini,A Banerjee,M Markicevic,G Provenzano,M A Basson,M Pagani,M L Scattoni,D Pozzi,N Wenderoth,A Galbusera,M Rudin,J P Lerch,M Matteoli,J Ellegood,A Gozzi

doi:10.1038/s41380-021-01245-4

Abstract

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social, communication and behavioral challenges often accompanied by additional co-morbidities that together negatively impact the quality of life of affected individuals and their families
A growing number of studies in idiopathic [7, 8] as well as syndromic forms of ASD [9,10,11,12] has suggested that aberrant connectivity in ASD could be detected by resting-state fMRI
One outstanding question in the field is whether ASD can be associated with a univocal, diagnosisspecific signature of dysfunctional brain connectivity that is common to the whole spectrum, or whether clinical heterogeneity is the sum of distinct and separable signatures of network dysfunction

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by social, communication and behavioral challenges often accompanied by additional co-morbidities that together negatively impact the quality of life of affected individuals and their families. These observations suggest an interpretative framework in which ASD-relevant etiological and genetic risk factors could lead to distinct network signatures of brain dysfunction, explaining heterogeneous connectivity alterations observed in clinical cohorts.

Objectives

Results

Conclusion