Frontal hypoconnectivity in the 16p11.2 microdeletion autism model

Autism spectrum disorder (ASD) has been often associated to the presence of reduced or aberrant functional brain connectivity as measured with resting state functional Magnetic Resonance Imaging (rsfMRI). However, great heterogeneity exists in the distribution and expression of these alterations, and little is known on the pathophysiological and genetic determinants underlying these deficits. Human chromosome 16p11.2 microdeletion, a trait associated to mild intellectual disability, is the most common gene copy number variation in autism, accounting for approximately 0.5-1% of all ASD cases. By using rsfMRI in a mouse model of human chromosome 16p11.2 microdeletion, we show that this genetic alteration results in circuit specific functional connectivity reductions. Specifically, we show that 16p11.2+/- mice exhibit reduced rsfMRI connectivity between retrosplenial and dorsal prefrontal areas of the mouse “default mode network”. Similarly reduced connectivity was observed between insular and prefrontal portions of the mouse “salience network”. Evidence of reduced thalamo-prelimbic connectivity was also observed. No genotype-dependent inter-hemispheric, fronto-hippocampal, and local connectivity differences were recorded. Collectively, our findings recapitulate hallmark neuroimaging findings in ASD and identify plausible macroscale circuital alterations underlying some of the cognitive deficits produced by 16p11.2 microdeletion.