title: 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.affiliation: Laboratoire Plasticité et Physio-Pathologie de la Motricité (UMR6196), Centre National de la Recherche Scientifique (CNRS) & Aix-Marseille Université, Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Boulenguez
authors.forename: Sylvie
authors.initials: S
authors.lastname: Liabeuf
authors.forename: Rémi
authors.initials: R
authors.lastname: Bos
authors.forename: Hélène
authors.initials: H
authors.lastname: Bras
authors.forename: Céline
authors.initials: C
authors.lastname: Jean-Xavier
authors.forename: Cécile
authors.initials: C
authors.lastname: Brocard
authors.forename: Aurélie
authors.initials: A
authors.lastname: Stil
authors.forename: Pascal
authors.initials: P
authors.lastname: Darbon
authors.forename: Daniel
authors.initials: D
authors.lastname: Cattaert
authors.forename: Eric
authors.initials: E
authors.lastname: Delpire
authors.forename: Martin
authors.initials: M
authors.lastname: Marsala
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinay
mesh_terms: 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
chemical_list: 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