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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, Alice Bertero, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Noemi Barsotti, Stefano Panzeri, Maria Luisa Scattoni, Massimo Pasqualetti, View ORCID ProfileAlessandro Gozzi
doi: https://doi.org/10.1101/060335
Adam Liska
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
2CIMeC, Center for Mind/Brain Sciences, University of Trento, Rovereto, Italy
MSc
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Alice Bertero
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
3Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy
PhD
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Ryszard Gomolka
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
MSc
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Mara Sabbioni
4Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Rome, Italy
MSc
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Alberto Galbusera
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
MSc
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Noemi Barsotti
3Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy
MSc
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Stefano Panzeri
5Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
PhD
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Maria Luisa Scattoni
4Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Department of Cell Biology and Neurosciences, Rome, Italy
PhD
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Massimo Pasqualetti
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
3Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy
PhD
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Alessandro Gozzi
1Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy
PhD
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  • ORCID record for Alessandro Gozzi
  • For correspondence: alessandro.gozzi@iit.it
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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 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 (DMN), 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.

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Posted January 18, 2017.
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Homozygous loss of autism-risk gene CNTNAP2 results in reduced local and long-range prefrontal functional connectivity
Adam Liska, Alice Bertero, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Noemi Barsotti, Stefano Panzeri, Maria Luisa Scattoni, Massimo Pasqualetti, 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, Alice Bertero, Ryszard Gomolka, Mara Sabbioni, Alberto Galbusera, Noemi Barsotti, Stefano Panzeri, Maria Luisa Scattoni, Massimo Pasqualetti, Alessandro Gozzi
bioRxiv 060335; doi: https://doi.org/10.1101/060335

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