Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury.
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.
Boulenguez
Pascale
P
Laboratoire Plasticité et Physio-Pathologie de la Motricité (UMR6196), Centre National de la Recherche Scientifique (CNRS) & Aix-Marseille Université, Marseille, France.
Liabeuf
Sylvie
S
Bos
Rémi
R
Bras
Hélène
H
Jean-Xavier
Céline
C
Brocard
Cécile
C
Stil
Aurélie
A
Darbon
Pascal
P
Cattaert
Daniel
D
Delpire
Eric
E
Marsala
Martin
M
Vinay
Laurent
L
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D005998:Glycine / Q000502:physiology; D007192:Indenes / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D009128:Muscle Spasticity / Q000503:physiopathology*; D051381:Rats; D012021:Reflex, Abnormal / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000096922:K Cl- Cotransporters
D019208:Brain-Derived Neurotrophic Factor; D002264:Carboxylic Acids; D018118:Chloride Channels; D005998:Glycine; D007192:Indenes; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C059990:((dihydroindenyl)oxy)alkanoic acid