Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human

Brain, May 2018
Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human.

Bertero A ^1,2 , Liska A ¹ , Pagani M ¹ , Parolisi R ³ , Masferrer ME ⁴ , Gritti M ⁵ , Pedrazzoli M ⁵ , Galbusera A ¹ , Sarica A ⁶ , Cerasa A ^6,7 , Buffelli M ⁸ , Tonini R ⁵ , Buffo A ³ , Gross C ⁴ , Pasqualetti M ^1,2 , Gozzi A ¹ .

Recent human genetic studies indicate that different variants increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk.

In this study, we focused our attention on chromosome 16p11.2 microdeletion, one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data, our collaborators showed that 16p11.2 microdeletion carriers exhibit impaired prefrontal connectivity, associated with socio-cognitive impairments. To corroborate human findings, they probed prefrontal connectivity and microstructural white integrity in a mouse model of 16p11.2 deletion by MRI and DTI. Our contribution concerns the electron microscopy analysis of myelin that revealed an increased axonal diameter in callosal fibers as a possible cellular correlate of these alterations

These results suggest that 16p11.2 microdeletion can predispose to neurodevelopmental disorders and cognitive disability through a dysregulation of prefrontal connectivity.

Comparable white matter microstructural abnormalities in human 16p11.2 deletion carriers and 16p11.2+/- mice.
(A) White matter regions exhibiting significantly increased connettivity in human deletion carriers (left, modified from Owen et al. 2014, with permission). The analysis in mouse revealed analogous increases in 16p11.2 + /- mutants (right). (B) Transmission electron micrographs of corpus callosum cross-sections from control (+/+) and 16p11.2 + /- (+/-) mice. Scale bar = 1 mm; original magnification 25 000. (C) Quantification of fractional anisotropy, mean thickness, axonal diameter and G-ratio in callosal neurons (*P<0.05, **P<0.01, means ± SEM).

¹ Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @UniTn, Rovereto, Italy.
² Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.
³ Department of Neuroscience Rita Levi-Montalcini- University of Torino, Neuroscience Institute Cavalieri Ottolenghi (NICO), Torino, Italy.
⁴ Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy.
⁵ Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
⁶ Consiglio Nazionale delle Ricerche, Catanzaro, Italy.
⁷ S. Anna Institute and Research in Advanced Neuro-rehabilitation (RAN) Crotone, Italy.
⁸ Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy.