4.7 Article

Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury

Journal

BRAIN
Volume 136, Issue -, Pages 3347-3361

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/brain/awt204

Keywords

spinal cord injury; neuronal dysfunction; exhaustion of locomotor activity; compensatory plasticity; syndromic analysis

Funding

  1. National Center of Competence in Research (NCCR) Plasticity and Repair of the Swiss National Science Foundation
  2. Starting Grant from the European Research Council [Walk Again] [ERC 261247]
  3. Neuroscience Centre Zurich (ZNZ)
  4. European Community's Seventh Framework Program [NEUWalk] [CP-IP 258654]
  5. Swiss National Science Foundation [subside 310030_130850]

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Severe spinal cord injury in humans leads to a progressive neuronal dysfunction in the chronic stage of the injury. This dysfunction is characterized by premature exhaustion of muscle activity during assisted locomotion, which is associated with the emergence of abnormal reflex responses. Here, we hypothesize that undirected compensatory plasticity within neural systems caudal to a severe spinal cord injury contributes to the development of neuronal dysfunction in the chronic stage of the injury. We evaluated alterations in functional, electrophysiological and neuromorphological properties of lumbosacral circuitries in adult rats with a staggered thoracic hemisection injury. In the chronic stage of the injury, rats exhibited significant neuronal dysfunction, which was characterized by co-activation of antagonistic muscles, exhaustion of locomotor muscle activity, and deterioration of electrochemically-enabled gait patterns. As observed in humans, neuronal dysfunction was associated with the emergence of abnormal, long-latency reflex responses in leg muscles. Analyses of circuit, fibre and synapse density in segments caudal to the spinal cord injury revealed an extensive, lamina-specific remodelling of neuronal networks in response to the interruption of supraspinal input. These plastic changes restored a near-normal level of synaptic input within denervated spinal segments in the chronic stage of injury. Syndromic analysis uncovered significant correlations between the development of neuronal dysfunction, emergence of abnormal reflexes, and anatomical remodelling of lumbosacral circuitries. Together, these results suggest that spinal neurons deprived of supraspinal input strive to re-establish their synaptic environment. However, this undirected compensatory plasticity forms aberrant neuronal circuits, which may engage inappropriate combinations of sensorimotor networks during gait execution.

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