Early limb unloading elicits long-term motor deficits involving motorneuron hyperexcitability associated with persistent alterations in glutamatergic synaptic plasticity in spinal cord injury

Authors: *K. MORIOKA1,2, T. TAZOE3,2, J. HUIE1,4, J. HAEFELI1, C. A. ALMEIDA1, J. A. SACRAMENTO1, J. C. BRESNAHAN1, M. S. BEATTIE1, S. TANAKA5, T. OGATA2, A. R. FERGUSON1,4;

Lab Abstract:

Abnormal sensory afferent feedback from the lower extremities after spinal cord injury (SCI) has potential to induce neuronal dysfunction that contributes to long-term motor deficits. Here, we investigated the impact of aberrant afferent input after SCI using hindlimb unloading early after mild contusive thoracic injury in adult female SD rats (T9; 50 kdyn IH). Three days post-injury, subjects were randomized to two experimental groups: 1) hindlimb unloading (HU) by tail suspension for 2 weeks followed by normal-loading for 6 weeks, or 2) normal-loading control for 8 weeks. Outcome assessments included: i) BBB open-field scoring and kinematic gait analysis; ii) electrophysiological H-reflex testing; iii) biomolecular and automated high-resolution confocal microscopy analysis of plasticity-related changes in lumbar ventral horn motor neurons. The results demonstrated that HU worsened impairment of hindlimb coordination after unloading (BBB = 12 for HU vs 17 for normal-loading controls). H-reflex testing of hindlimb muscles at 8 weeks showed that HU induced chronic hyper-excitability of spinal reflex circuitry. Quantitative biochemistry of ventral spinal synaptoneurosomes revealed a chronic increase in AMPA receptor (AMPAR) subunit GluA1 serine 831 phosphorylation, while quantitative immunohistochemistry revealed a chronic increase in GluA1 at synaptic sites on spinal motoneurons, suggesting that HU induced maladaptive plasticity in the spinal cord. Data-driven multidimensional analysis identified strong association between AMPAR over-drive on motorneurons and time-dependent motor recovery, chronic motorneuron hyper-excitability after HU. Our findings suggest that early unloading-induced aberrant afferent input after SCI can worsen maladaptive plasticity undermining long-term recovery, and provide a mechanistic rationale for early post-SCI intervention with weight-bearing training for precision rehabilitation.

*K. MORIOKA1,2, T. TAZOE3,2, J. HUIE1,4, J. HAEFELI1, C. A. ALMEIDA1, J. A. SACRAMENTO1, J. C. BRESNAHAN1, M. S. BEATTIE1, S. TANAKA5, T. OGATA2, A. R. FERGUSON1,4;

1Dept. of Neurolog. Surgery, Brain and Spinal Injury Ctr. (BASIC), UCSF, San Francisco, CA; 2Dept. of Rehabil. for the Movement Functions, Res. Institute, Natl. Rehabil. Ctr. for the Persons with Disabilities, Saitama, Japan; 3Neural Prosthesis Project, Tokyo Metropolitan Inst. of Med. Sci., Tokyo, Japan; 4San Francisco Veterans Affairs Med. Ctr., San Francisco, CA; 5Dept. of Orthopaedic Surgery, The Univ. of Tokyo, Tokyo, Japan.

Grant Support:NIH Grant NS067092 (ARF), NIH Grant NS069537 (ARF), NIH Grant NS088475 (ARF), Wings for Life Spinal Cord Research Foundation WFLUS013/13 (KM), Wings for Life Spinal Cord Research Foundation WFLUS008/12, WFLUS 006/14 (ARF), Craig H. Neilsen Foundation 224308 (ARF), Craig H. Neilsen Foundation 313739 (JH), UCSF Core Center for Musculoskeletal Biology and Medicine P30AR066262 (ARF/KM)

Program No. 213.27. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.

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