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Homozygous loss of autism-risk gene CNTNAP2 results in reduced local and long-range prefrontal functional connectivity

View ORCID ProfileAdam Liska, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Stefano Panzeri, Maria Luisa Scattoni, View ORCID ProfileAlessandro Gozzi
doi: https://doi.org/10.1101/060335
Adam Liska
1Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems@UniTn, 38068, Rovereto, ITALY
2CIMEC, Center for Mind/Brain Sciences, University of Trento, Rovereto, Italy
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Ryszard Gomolka
1Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems@UniTn, 38068, Rovereto, ITALY
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Mara Sabbioni
3Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Rome, ITALY
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Alberto Galbusera
1Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems@UniTn, 38068, Rovereto, ITALY
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Stefano Panzeri
4Neural Computation Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems@UniTn, 38068, Rovereto, ITALY
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Maria Luisa Scattoni
3Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Rome, ITALY
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Alessandro Gozzi
1Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems@UniTn, 38068, Rovereto, ITALY
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  • ORCID record for Alessandro Gozzi
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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.

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Posted June 29, 2016.
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Homozygous loss of autism-risk gene CNTNAP2 results in reduced local and long-range prefrontal functional connectivity
Adam Liska, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Stefano Panzeri, Maria Luisa Scattoni, Alessandro Gozzi
bioRxiv 060335; doi: https://doi.org/10.1101/060335
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Homozygous loss of autism-risk gene CNTNAP2 results in reduced local and long-range prefrontal functional connectivity
Adam Liska, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Stefano Panzeri, Maria Luisa Scattoni, Alessandro Gozzi
bioRxiv 060335; doi: https://doi.org/10.1101/060335

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