Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity
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Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity. / Liska, Adam; Bertero, Alice; Gomolka, Ryszard; Sabbioni, Mara; Galbusera, Alberto; Barsotti, Noemi; Panzeri, Stefano; Scattoni, Maria Luisa; Pasqualetti, Massimo; Gozzi, Alessandro.
In: CEREB CORTEX, Vol. 28, No. 4, 01.04.2018, p. 1141-1153.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity
AU - Liska, Adam
AU - Bertero, Alice
AU - Gomolka, Ryszard
AU - Sabbioni, Mara
AU - Galbusera, Alberto
AU - Barsotti, Noemi
AU - Panzeri, Stefano
AU - Scattoni, Maria Luisa
AU - Pasqualetti, Massimo
AU - Gozzi, Alessandro
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - Animals
KW - Autistic Disorder/genetics
KW - Brain Mapping
KW - Diffusion Magnetic Resonance Imaging
KW - Disease Models, Animal
KW - Female
KW - Image Processing, Computer-Assisted
KW - Interpersonal Relations
KW - Luminescent Proteins/genetics
KW - Magnetic Resonance Imaging
KW - Male
KW - Membrane Proteins/genetics
KW - Mice
KW - Mice, Transgenic
KW - Mutation/genetics
KW - Nerve Net/diagnostic imaging
KW - Nerve Tissue Proteins/genetics
KW - Neural Pathways/diagnostic imaging
KW - Oxygen/blood
KW - Prefrontal Cortex/diagnostic imaging
KW - Transduction, Genetic
KW - White Matter/diagnostic imaging
U2 - 10.1093/cercor/bhx022
DO - 10.1093/cercor/bhx022
M3 - SCORING: Journal article
C2 - 28184409
VL - 28
SP - 1141
EP - 1153
JO - CEREB CORTEX
JF - CEREB CORTEX
SN - 1047-3211
IS - 4
ER -