Abstract
Functional connectivity aberrancies, as measured with resting-state fMRI (rsfMRI), have been consistently observed in the brain of autism spectrum disorders (ASD) patients. However, the genetic and neurobiological underpinnings of these findings remain unclear. Homozygous mutations in Contactin Associated Protein-like 2 (CNTNAP2), a neurexin-related cell-adhesion molecule, are strongly linked to autism and epilepsy. Here we used high field rsfMRI to show that homozygous mice lacking CNTNAP2 exhibit reduced long-range and local functional connectivity in prefrontal and midline “functional hubs” of the mouse brain. Long-range rsfMRI connectivity impairments affected heteromodal cortical regions and were prominent between frontal and posterior components of the mouse default mode network (DMN), an effect that was associated with reduced social investigation, a core “autism trait” in mice. We did not observe genotype-dependent differences in cortico-cortical white matter connectivity as measured with MRI-based fibre tractography, thus supporting a functional origin for the observed rsfMRI desynchronization. These findings reveal a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of functional coupling between integrative heteromodal cortical areas.
