Autism-associated <i>Scn2a</i> haploinsufficiency disrupts in vivo dendritic signaling and impairs flexible decision-making.

Abstract

<i>SCN2A</i> is a high-confidence risk gene for autism spectrum disorder. Loss-of-function mutations in <i>Scn2a</i> reduce dendritic excitability in neocortical pyramidal cells. However, the impact of <i>Scn2a</i> 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. <i>Scn2a^+/-</i> 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, <i>Scn2a^+/-</i> mice were inflexible in the face of changing competitive pressure. Apical dendritic tuft in intratelencephalic neurons typically encoded reward and strategy, but these task-specific representations were altered in <i>Scn2a^+/-</i> mice. Collectively, the findings demonstrate that <i>Scn2a</i> haploinsufficiency weakens dendritic integration in vivo and disrupts dendritic encoding of task variables during flexible decision-making.