HUMAN-SPECIFIC AND ACTIVITY-DEPENDENT REGULATION OF CORTICAL CONNECTIVITY

Human cognitive abilities rely on specialized features of neurons and circuits that emerged during human evolution. These features reflect human-specific regulations of neuronal and synaptic development. Yet, their underlying molecular mechanisms remain largely unknown. Here, we characterize the role of FRMPD2B (FERM and PDZ Domain containing 2B), a human-specific gene produced by partial duplication during the transition between Australopithecus and Homo. FRMPD2B is almost exclusively expressed in cortico-projecting excitatory neurons of the neocortex during the period of neuronal morphogenesis and synaptogenesis, but its role has never been investigated. Using targeted in utero electroporation to sparsely express FRMPD2B in mouse L2/3 cortical pyramidal neurons, we demonstrate that it increases dendritic and axonal branching and synapse number, indicating that FRMPD2B-expressing neurons receive and send more information. Furthermore, we show that during evolution, FRMPD2B became experience- and activity-responsive through the insertion of retrotransposon. Together, our results reveal novel mechanisms through which a human-specific modifier partakes in experience-dependent expansion of cortico-cortical connectivity, opening new avenues to understand the unique complexity of the human brain.