RT Journal Article SR Electronic T1 Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice JF bioRxiv FD Cold Spring Harbor Laboratory SP 143552 DO 10.1101/143552 A1 Philipp Suetterlin A1 Shaun Hurley A1 Conor Mohan A1 Kimberley L. H. Riegman A1 Angela Caruso A1 Marco Pagani A1 Jacob Ellegood A1 Alberto Galbusera A1 Ivan Crespo-Enriquez A1 Caterina Michetti A1 Robert Ellingford A1 Olivier Brock A1 Alessio Delogu A1 Philippa Francis-West A1 Jason P. Lerch A1 Maria Luisa Scattoni A1 Alessandro Gozzi A1 Cathy Fernandes A1 M. Albert Basson YR 2017 UL http://biorxiv.org/content/early/2017/05/29/143552.abstract AB Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.