Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain

Cells. 2022 Sep 17;11(18):2910. doi: 10.3390/cells11182910.


The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modification that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl- in the postsynaptic neuron. As the intracellular concentration increases, the inward flow of Cl- through an ionotropic GABA-A receptor is reduced, which decreases its hyperpolarizing (inhibitory) effect, a modulatory effect known as ionic plasticity. The loss of GABA-dependent inhibition enables a state of over-excitation within the spinal cord that fosters aberrant motor activity (spasticity) and chronic pain. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome. Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic benefits.

Keywords: GABA; KCC2; addiction; epilepsy; ionic plasticity; pain; spasticity; spinal cord injury.

Publication types

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

MeSH terms

  • Brain / metabolism
  • Chlorides
  • Humans
  • Potassium
  • Receptors, GABA-A
  • Spinal Cord Injuries*
  • Symporters* / metabolism
  • gamma-Aminobutyric Acid / pharmacology


  • Chlorides
  • Receptors, GABA-A
  • Symporters
  • gamma-Aminobutyric Acid
  • Potassium

Grants and funding

This research was funded by the Mary Tucker Currie Professorship to J.W.G. and the National Institute of Neurological Disorders and Stroke (NS104422).