Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations

This study investigates why spared axons in incomplete spinal cord injuries fail to restore function. Researchers found that a drug, CLP290, that enhances the activity of a protein called KCC2, can restore stepping ability in paralyzed mice with specific spinal cord injuries. The recovery was linked to inhibitory interneurons, nerve cells that dampen activity, located around the injury site. Increasing KCC2 activity in these cells appears to re-establish a more normal balance of excitation and inhibition in the spinal cord, allowing brain signals to reach the legs. The scientists confirmed that directly reducing the excitability of these inhibitory interneurons had the same effect as the drug, suggesting that these cells are key to unlocking dormant spinal circuits after injury.

• 1
  CLP290, a KCC2 agonist, restores consistent stepping ability in paralyzed mice with staggered spinal cord lesions, but not in mice with complete spinal cord transection.
• 2
  Selective expression of KCC2 in inhibitory interneurons, particularly those located between and around the staggered lesions, mimics the effects of CLP290 and leads to functional recovery.
• 3
  Reducing the excitability of inhibitory interneurons using DREADD technology also mimics the effects of KCC2/CLP290, promoting functional recovery and altering neuronal activation patterns in the spinal cord.