Disruption of the transcription factor NEUROD2 causes an autism syndrome via cell-autonomous defects in cortical projection neurons

We identified seven families associatingNEUROD2pathogenic mutations with ASD and intellectual disability. To get insight into the pathophysiological mechanisms, we analyzed cortical development inNeurod2KO mice. Cortical projection neurons (CPNs) over-migrated during embryogenesis, inducing abnormal thickness and laminar positioning of cortical layers. At juvenile ages, dendritic spine turnover and intrinsic excitability were increased in L5 CPNs. Differentially expressed genes inNeurod2KO mice were enriched for voltage-gated ion channels, and the human orthologs of these genes were strongly associated with ASD. Furthermore, adultNeurod2KO mice exhibited core ASD-like behavioral abnormalities. Finally, by generatingNeurod2conditional mutant mice we demonstrate that forebrain excitatory neuron-specificNeurod2deletion recapitulates cellular and behavioral ASD phenotypes found in full KO mice. Our findings demonstrate crucial roles forNeurod2in cortical development and function, whose alterations likely account for ASD and related symptoms in the newly definedNEUROD2mutation syndrome.