Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Department of Orthopaedic Surgery, Orthopaedic Trauma Institute (OTI), University of California, San Francisco (UCSF), San Francisco, CA, USA
Toshiki Tazoe
Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Neural Prosthesis Project, Department of Brain and Neuroscience, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
J. Russell Huie
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Kentaro Hayakawa
Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Department of Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Orthopaedic and Spine Surgery, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
Rentaro Okazaki
Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Department of Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Orthopaedic Surgery, Saitama Red Cross Hospital, Saitama, Japan
Cristian F. Guandique
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Carlos A. Almeida
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Jenny Haefeli
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Makoto Hamanoue
Department of Physiology, Advanced Medical Research Center, Toho University School of Medicine, Tokyo, Japan
Takashi Endoh
Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Faculty of Development and Education, Uekusa Gakuen University, Chiba, Japan
Sakae Tanaka
Department of Orthopaedic Surgery, Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Jacqueline C. Bresnahan
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Michael S. Beattie
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA
Toru Ogata
Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Saitama, Japan; Department of Rehabilitation Medicine, The University of Tokyo Hospital, Tokyo, Japan; Corresponding author
Adam R. Ferguson
Department of Neurological Surgery, Weill Institute for Neurosciences, Brain and Spinal Injury Center (BASIC), University of California, San Francisco (UCSF), San Francisco, CA, USA; San Francisco Veterans Affairs Healthcare System (SFVAHCS), San Francisco, CA, USA; Corresponding author
Summary: Use-dependent plasticity after spinal cord injury (SCI) enhances neuromotor function, however, the optimal timing to initiate rehabilitation remains controversial. To test impacts of early disuse, we established a rodent model of transient hindlimb suspension in acute phase SCI. Early disuse in the first 2-week after SCI undermined recovery on open-field locomotion, kinematics, and swim tests even after 6-week of normal gravity reloading. Early disuse produced chronic spinal circuit hyper-excitability in H-reflex and interlimb reflex tests. Quantitative synaptoneurosome analysis of lumboventral spinal cords revealed shifts in AMPA receptor (AMPAR) subunit GluA1 localization and serine 881 phosphorylation, reflecting enduring synaptic memories of early disuse stored in the spinal cord. Automated confocal analysis of motoneurons revealed persistent shifts toward GluA2-lacking, calcium-permeable AMPARs in disuse subjects. Unsupervised machine learning associated multidimensional synaptic changes with persistent recovery deficits in SCI. The results argue for early aggressive rehabilitation to prevent disuse plasticity that limits SCI recovery.
