title: Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity.
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.
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.|CIMeC, Center for Mind/Brain Sciences, University of Trento, Rovereto 38068, Italy.
authors.forename: Adam
authors.initials: A
authors.lastname: Liska
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.|Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa 56127, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertero
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Gomolka
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Rome 00161, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Sabbioni
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Galbusera
authors.affiliation: Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa 56127, Italy.
authors.forename: Noemi
authors.initials: N
authors.lastname: Barsotti
authors.affiliation: Neural Computation Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Panzeri
authors.affiliation: Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Neurotoxicology and Neuroendocrinology Section, Rome 00161, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Scattoni
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.|Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa 56127, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pasqualetti
authors.affiliation: Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D001931:Brain Mapping; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D005260:Female; D007091:Image Processing, Computer-Assisted; D007398:Interpersonal Relations; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009415:Nerve Net / Q000000981:diagnostic imaging / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging*; D014161:Transduction, Genetic; D066127:White Matter / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000097573:Red Fluorescent Protein
chemical_list: D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010100:Oxygen; D000097573:Red Fluorescent Protein; C568163:CNTNAP2 protein, mouse