Autism-associatedScn2ahaploinsufficiency disruptsin vivodendritic signaling and impairs flexible decision-making

SCN2Ais a high-confidence risk gene for autism spectrum disorder. Loss-of-function mutations inScn2areduce dendritic excitability in neocortical pyramidal cells. However, the impact ofScn2ahaploinsufficiency on dendritic signalingin vivo, particularly during behavior, is unknown. In this study, we used two-photon microscopy to image dendritic calcium transients in deep layer pyramidal cells in the mouse medial frontal cortex.Scn2a^+/-mice had diminished coupling between apical and proximal dendritic compartments. Pyramidal tract neurons had abnormal event rates, while intratelencephalic neurons had compartment-specific alterations indicative of diminished dendritic integration. In a matching pennies task,Scn2a^+/-mice were inflexible in the face of changing competitive pressure. Apical dendritic tuft in IT neurons typically encoded reward and strategy, but these task-specific representations were absent inScn2a^+/-mice. Collectively, the findings demonstrate thatScn2ahaploinsufficiency weakens dendritic integrationin vivoand disrupts the dendritic encoding of decision variables, potentially contributing to the cognitive rigidity in autism spectrum disorder.