Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury

Exp Neurol. 2021 Apr;338:113605. doi: 10.1016/j.expneurol.2021.113605. Epub 2021 Jan 13.


After spinal cord injury (SCI), the majority 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 a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. 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 in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.

Keywords: CLP257; Chloride homeostasis; KCC2; Neuroplasticity; Rehabilitation; Spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autonomic Dysreflexia / etiology
  • Autonomic Dysreflexia / metabolism*
  • Muscle Spasticity / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord Injuries / metabolism*
  • Symporters / metabolism*
  • Thiazolidines / pharmacology


  • CLP257
  • Symporters
  • Thiazolidines
  • potassium-chloride symporters