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Cereb Cortex. 2018 Apr 1;28(4):1141-1153. doi: 10.1093/cercor/bhx022.

Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity.

Author information

1
Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.
2
CIMeC, Center for Mind/Brain Sciences, University of Trento, Rovereto 38068, Italy.
3
Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa 56127, Italy.
4
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Rome 00161, Italy.
5
Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.

Abstract

Functional connectivity aberrancies, as measured with resting-state functional magnetic resonance imaging (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 protein, are strongly linked to autism and epilepsy. Here we used rsfMRI to show that homozygous mice lacking Cntnap2 exhibit reduced long-range and local functional connectivity in prefrontal and midline brain "connectivity hubs." Long-range rsfMRI connectivity impairments affected heteromodal cortical regions and were prominent between fronto-posterior components of the mouse default-mode network, an effect that was associated with reduced social investigation, a core "autism trait" in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex of Cntnap2-/- mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white-matter organization appeared to be otherwise preserved in these animals. 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 connectivity in integrative prefrontal areas.

PMID:
28184409
DOI:
10.1093/cercor/bhx022

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