Developmentally primed cortical neurons maintain fidelity of differentiation and establish appropriate functional connectivity after transplantation

Repair of complex CNS circuitry will require newly incorporated neurons to become appropriately, functionally integrated. One approach is to direct differentiation of endogenous progenitors in situ, or ex vivo followed by transplantation. Prior studies find that newly incorporated neurons can establish long-distance axon projections, form synapses, and functionally integrate in evolutionarily old hypothalamic energy balance circuitry. We now demonstrate that postnatal neocortical connectivity can be reconstituted with point-to-point precision, including cellular integration of specific, molecularly identified projection neuron subtypes into correct position, combined with development of appropriate long-distance projections and synapses. Using optogenetics-based electrophysiology, experiments demonstrate functional afferent and efferent integration of transplanted neurons into trans-callosal projection neuron circuitry. Results further indicate that “primed” early postmitotic neurons, including already fate-restricted deep layer projection neurons and/or plastic post-mitotic neuroblasts with partially fate-restricted potential, account for the predominant population of neurons capable of achieving this optimal level of integration.