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bioRxiv · 10.1101/489740

Exercise restores chloride homeostasis and decreases spasticity through the BDNF-KCC2 pathway after chronic SCI

Schulze, H.·Choyke, S.·Klaszky, M.·Cote, M.-P.
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Abstract

Activity-based therapies are routinely integrated in rehabilitation programs to induce repetitive activation of the neuromuscular system and facilitate functional recovery after spinal cord injury (SCI). Among the beneficial effects of physical therapy is a reduction of hyperreflexia and spasticity in SCI individuals, but the precise mechanism by which exercise regulates spinal networks and facilitate recovery remains elusive. Spasticity is a debilitating condition that affects ~ 75% of the SCI population and interferes with residual motor function. Current pharmacological treatments not only have serious side effects but also actively depress spinal excitability and interferes with motor recovery. Understanding how activity-based therapies contribute to decrease spasticity will help identify critical pharmacological targets and optimize rehabilitation programs.\n\nKCC2, a neuron-specific Cl- extruder, is critical to the maintenance of [Cl-]i and its downregulation after SCI leads to a shift in chloride homeostasis that contributes to develop spasticity. We have shown in earlier studies that not only exercise promotes reflex modulation but also restores KCC2 expression in motoneurons. KCC2 is dynamically modulated by several signaling pathways, the most prevalent being BDNF-TrkB. Interestingly, activity-dependent processes triggered by exercise include an increase in the expression of BDNF in the lumbar spinal cord. However, whether the increase in KCC2 contributes to functional recovery and rely on BDNF activity have not been established. Our objective was to determine 1) whether the activity-dependent upregulation of KCC2 contributes to decrease spasticity after SCI; 2) if BDNF regulates KCC2 expression in an activity-dependent manner.\n\nUsing a model of complete SCI, we investigated this possible causal effect by intrathecally delivering VU0240551, a specific KCC2 blocker, or TrkB-IgG, a BDNF scavenger. Drugs were specifically delivered during the daily rehabilitation sessions to transiently prevent KCC2/BDNF activity. We provide evidence that the beneficial effect of exercise on functional recovery relies on a BDNF-dependent increase in KCC2 expression on motoneurons and the restoration of endogenous inhibition to a mature state. We identify, for the first time, that the increase in KCC2 activity with activity-based therapies functionally contributes to H-reflex recovery and critically depends on BDNF activity. This provides a new perspective on our understanding of how exercise impact hyperreflexia by identifying the biological basis of recovery of function. Acting directly on chloride homeostasis through BDNF to restore endogenous inhibition rather than actively depress excitability can diminish the reduction in motor output associated with the current pharmacological management of SCI and improve the outcome of rehabilitation programs.

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Schulze, H., Choyke, S., Klaszky, M., Cote, M.-P.. 2018-12-07. Exercise restores chloride homeostasis and decreases spasticity through the BDNF-KCC2 pathway after chronic SCI. https://doi.org/10.1101/489740

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