PT  - JOURNAL ARTICLE
AU  - Philipp Suetterlin
AU  - Shaun Hurley
AU  - Conor Mohan
AU  - Kimberley L. H. Riegman
AU  - Marco Pagani
AU  - Angela Caruso
AU  - Jacob Ellegood
AU  - Alberto Galbusera
AU  - Ivan Crespo-Enriquez
AU  - Caterina Michetti
AU  - Robert Ellingford
AU  - Olivier Brock
AU  - Alessio Delogu
AU  - Philippa Francis-West
AU  - Jason P. Lerch
AU  - Maria Luisa Scattoni
AU  - Alessandro Gozzi
AU  - Cathy Fernandes
AU  - M. Albert Basson
TI  - Early postnatal brain overgrowth and gene expression changes prefigure functional over-connectivity of the cortex in <em>Chd8</em> haploinsufficient mice
AID  - 10.1101/143552
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 143552
4099  - http://biorxiv.org/content/early/2017/07/07/143552.short
4100  - http://biorxiv.org/content/early/2017/07/07/143552.full
AB  - Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. Here, we report that Chd8 heterozygous mice display subtle brain hyperplasia shortly after birth, hypertelorism, early motor delay, pronounced hypoactivity and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at mid-gestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the down-regulated transcripts. Resting-state functional MRI identified increased synchronised activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioural phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring result in distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have consistently found evidence for changes in functional connectivity in ASD cohorts, most commonly long-range under-connectivity. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.