RT Journal Article
SR Electronic
T1 Deletion of autism risk gene Shank3 disrupts prefrontal connectivity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 409284
DO 10.1101/409284
A1 Marco Pagani
A1 Alice Bertero
A1 Adam Liska
A1 Alberto Galbusera
A1 Mara Sabbioni
A1 Maria Luisa Scattoni
A1 Massimo Pasqualetti
A1 Alessandro Gozzi
YR 2018
UL http://biorxiv.org/content/early/2018/09/06/409284.abstract
AB Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in mice, here we show that loss of Shank3 (Shank3B-/-) results in disrupted local and long-range prefrontal functional connectivity, as well as fronto-striatal decoupling. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.