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Dissertation
Enhancing KCC2 Activity Restores Reflex Inhibition and Improves Locomotor Function after Spinal Cord Injury
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2021
DOI:
https://doi.org/10.17918/00000855
Abstract
After spinal cord injury (SCI), 70% of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca²⁺-dependent signaling, current anti-spastic medications lead to serious side effects, including muscle weakness and a drastic, indiscriminate decrease in spinal excitability which impairs motor function and recovery. Exercise, in contrast, decreases spastic symptoms without eliminating spinal excitability by increasing expression of the chloride co-transporter, KCC2, in lumbar motoneurons. However, exercise is not always possible for SCI individuals. Thus, a viable alternative may be to restore KCC2 activity pharmacologically. This work examines how the recently developed KCC2 enhancers, CLP257 and CLP290, affect spastic symptoms and motor function after chronic SCI. In Sprague Dawley rats with a complete thoracic injury, increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch. Furthermore, the improvements due to this acute pharmacological treatment mirrored those observed in rats that were exercised for four weeks. We then explored this further in awake, behaving animals, using chronically implanted electrodes to assess EMG responses in an array of pathways involved in motor control. Increasing KCC2 activity reduced co-contraction of antagonistic muscles, restored reflex responses that resemble those recorded pre-injury, and improved locomotor patterning without decreasing motor output. Together, our results suggest that by restoring endogenous inhibition, pharmacologically increasing KCC2 activity has potential to avoid severe side effects and improve the quality of life of affected individuals.
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Details
- Title
- Enhancing KCC2 Activity Restores Reflex Inhibition and Improves Locomotor Function after Spinal Cord Injury
- Creators
- Jadwiga N. Bilchak
- Contributors
- Marie-Pascale Côté (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 143 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Neurology; Drexel University
- Other Identifier
- 991015588562704721