The injury environment critically influences the brain-wide input connectome of transplanted neurons

Cell transplantation is a promising approach for reconstruction of neuronal circuits after brain damage. Transplanted neurons integrate with remarkable specificity into circuitries of the mouse cerebral cortex affected by neuronal ablation. However, it remains unclear how neurons perform in a local environment undergoing reactive gliosis, inflammation, macrophage infiltration and scar formation, as in brain trauma. To elucidate this, we transplanted cells from the embryonic murine cerebral cortex into stab-injured, inflamed-only, or intact cortex of adult mice. Brain-wide quantitative connectomics unraveled graft inputs from correct regions across the brain in all conditions, with pronounced quantitative differences: scarce in intact or inflamed brain, versus exuberant after trauma. In the latter, excessive synapse pruning follows the initial overshoot of connectivity resulting in only a few input connections left. Proteomic profiling identifies candidate molecules involved in the synaptic yield, a pivotal parameter to tailor for functional restoration of neuronal circuits.