Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury.

Abstract

Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl-) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.

• Authors: Pascale Boulenguez, Sylvie Liabeuf, Rémi Bos, Hélène Bras, Céline Jean-Xavier, Cécile Brocard, Aurélie Stil, Pascal Darbon, Daniel Cattaert, Eric Delpire, Martin Marsala, Laurent Vinay
• Journal: Nature medicine (Nat Med) Vol. 16 Issue 3 Pg. 302-7 (Mar 2010) ISSN: 1546-170X [Electronic] United States
• PMID: 20190766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ((dihydroindenyl)oxy)alkanoic acid
• Brain-Derived Neurotrophic Factor
• Carboxylic Acids
• Chloride Channels
• Indenes
• Symporters
• potassium-chloride symporters
• gamma-Aminobutyric Acid
• Glycine

Topics

• Animals
• Blotting, Western
• Brain-Derived Neurotrophic Factor (pharmacology)
• Carboxylic Acids (pharmacology)
• Chloride Channels (drug effects, physiology)
• Down-Regulation (physiology)
• Female
• Gene Expression Regulation
• Glycine (physiology)
• Indenes (pharmacology)
• Injections, Spinal
• Male
• Membrane Potentials (physiology)
• Mice
• Mice, Transgenic
• Motor Neurons (physiology)
• Muscle Spasticity (physiopathology)
• Rats
• Reflex, Abnormal (drug effects, physiology)
• Spinal Cord (physiopathology)
• Spinal Cord Injuries (physiopathology)
• Symporters (antagonists & inhibitors, biosynthesis, physiology)
• gamma-Aminobutyric Acid (physiology)