Abstract

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.

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Acknowledgements

We would like to thank Z. He, B. Zheng, F. Wang, L. Wang and the members of the Zou lab for critical reading of the manuscript, as well as comments and suggestions. This work was supported by grants to Y.Z. (RO1 NS047484, R21 NS081738, Wings for Life Foundation, and International Foundation for Research in Paraplegia).

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Author notes

    • Edmund R Hollis II
    •  & Shih-Hsiu Wang

    Present addresses: Burke Medical Research Institute, White Plains, New York, USA, and Brain and Mind Research Institute at Weill Cornell Medicine, New York, New York, USA (E.R.H.); Department of Pathology and Cell Biology, Columbia University School of Medicine, New York, New York, USA (S.-H.W.).

Affiliations

  1. Neurobiology Section, Biological Sciences Division, University of California, San Diego, La Jolla, California, USA.

    • Edmund R Hollis II
    • , Nao Ishiko
    • , Ting Yu
    • , Chin-Chun Lu
    • , Ariela Haimovich
    • , Kristine Tolentino
    • , Alisha Richman
    • , Anna Tury
    • , Maysam Pessian
    • , Euna Jo
    •  & Yimin Zou
  2. Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

    • Shih-Hsiu Wang
    •  & Alex Kolodkin

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Contributions

Y.Z. and E.R.H. designed the experiments. E.R.H., N.I., T.Y., C.-C.L., A.H., K.T., A.R., A.T., M.P. and E.J. performed all the experiments under the supervision of Y.Z. Y.Z. designed the antigen for the Ryk monoclonal antibody. C.-C.L. and A.R. prepared the antigen. S.-H.W. generated the hybridomas using the antigen under the supervision of A.K. A.T. and E.R.H. screened for the hybridoma and tested the function of the Ryk monoclonal antibody in vitro and in vivo.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yimin Zou.

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DOI

https://doi.org/10.1038/nn.4282