Autism-associated Scn2a haploinsufficiency disrupts in vivo dendritic signaling and impairs flexible decision-making

ABSTRACT SCN2A is a high-confidence risk gene for autism spectrum disorder. Loss-of-function mutations in Scn2a reduce dendritic excitability in neocortical pyramidal cells. However, the impact of Scn2a haploinsufficiency on dendritic signaling in 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 altered in Scn2a +/- mice. Collectively, the findings demonstrate that Scn2a haploinsufficiency weakens dendritic integration in vivo and disrupts the dendritic encoding of decision variables, potentially contributing to the cognitive rigidity in autism spectrum disorder.