The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivity

The human neocortex is characterized by its uniquely prolonged postnatal developmental period during which experience sculpts neuronal circuits, a process essential to human cognitive abilities. Yet whether human-specific genetic innovations have shaped the activity-dependent mechanisms regulating circuit assembly remains unknown. Here, we identify the human-specific gene FRMPD2B as an activity- and experience-regulated modifier of cortical connectivity. FRMPD2B is primarily expressed in cortico-cortical projection neurons postnatally and throughout childhood. It promotes dendritic, axonal and synaptic development, and is required for proper morphogenesis in xenotransplanted human cortical neurons. FRMPD2B expression is bidirectionally regulated by neuronal activity and experience. This activity-responsiveness was gained after FRMPD2B arose through partial gene duplication, when a retrotransposon insertion remodeled its promoter. Our findings highlight how a series of genetic innovations have led to the emergence of a human-specific activity-regulated developmental program through which postnatal experience drives cortical connectivity expansion, linking genome evolution to human brain plasticity.