Ryk controls remapping of motor cortex during functional recovery after spinal cord injury

Mechanisms underlying partial functional recovery after spinal cord injury are unclear. Conditionally knocking out the reinduced repulsive axon guidance receptor Ryk led to increased corticospinal axon plasticity and functional recovery. Motor cortex reorganized such that the hindlimb cortex controls the forelimb with continued forelimb reaching task training. A greater cortical area was recruited to control the forelimb in Ryk cKO. Limited functional recovery can be achieved through rehabilitation after incomplete spinal cord injury. Eliminating the function of a repulsive Wnt receptor, Ryk, in mice and rats by either conditional knockout in the motor cortex or monoclonal antibody infusion resulted in increased corticospinal axon collateral branches with presynaptic puncta in the spinal cord and enhanced recovery of forelimb reaching and grasping function following a cervical dorsal column lesion. Using optical stimulation, we observed that motor cortical output maps underwent massive changes after injury and that hindlimb cortical areas were recruited to control the forelimb over time. Furthermore, a greater cortical area was dedicated to controlling the forelimb in Ryk conditional knockout mice than in controls (wild-type or heterozygotes). In the absence of weekly task-specific training, recruitment of ectopic cortical areas was greatly reduced and there was no significant functional recovery even in Ryk conditional knockout mice. Our study provides evidence that maximal circuit reorganization and functional recovery can be achieved by combining molecular manipulation and targeted rehabilitation.