title: Exercise modulates chloride homeostasis after spinal cord injury.
abstract: Activity-based therapies are routinely integrated in spinal cord injury (SCI) rehabilitation programs because they result in a reduction of hyperreflexia and spasticity. However, the mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve functional recovery are poorly understood. Persisting alterations in the action of GABA on postsynaptic targets is a signature of CNS injuries, including SCI. The action of GABA depends on the intracellular chloride concentration, which is determined largely by the expression of two cation-chloride cotransporters (CCCs), KCC2 and NKCC1, which serve as chloride exporters and importers, respectively. We hypothesized that the reduction in hyperreflexia with exercise after SCI relies on a return to chloride homeostasis. Sprague Dawley rats received a spinal cord transection at T12 and were assigned to SCI-7d, SCI-14d, SCI-14d+exercise, SCI-28d, SCI-28d+exercise, or SCI-56d groups. During a terminal experiment, H-reflexes were recorded from interosseus muscles after stimulation of the tibial nerve and the low-frequency-dependent depression (FDD) was assessed. We provide evidence that exercise returns spinal excitability and levels of KCC2 and NKCC1 toward normal levels in the lumbar spinal cord. Acutely altering chloride extrusion using the KCC2 blocker DIOA masked the effect of exercise on FDD, whereas blocking NKCC1 with bumetanide returned FDD toward intact levels after SCI. Our results indicate that exercise contributes to reflex recovery and restoration of endogenous inhibition through a return to chloride homeostasis after SCI. This lends support for CCCs as part of a pathway that could be manipulated to improve functional recovery when combined with rehabilitation programs.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129 marie-pascale.cote@drexelmed.edu.
authors.forename: Marie-Pascale
authors.initials: MP
authors.lastname: Côté
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
authors.forename: Sapan
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
authors.forename: Marina
authors.initials: M
authors.lastname: Zambrotta
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
authors.forename: John D
authors.initials: JD
authors.lastname: Houlé
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D002034:Bumetanide / Q000494:pharmacology; D018118:Chloride Channels / Q000378:metabolism; D002712:Chlorides / Q000502:physiology*; D002818:Cordotomy; D005081:Exercise Therapy; D005260:Female; D005786:Gene Expression Regulation; D006181:H-Reflex / Q000187:drug effects; D006706:Homeostasis; D007192:Indenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000503:physiopathology / Q000534:rehabilitation; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013979:Tibial Nerve / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D000085:Acetates; D019208:Brain-Derived Neurotrophic Factor; D002034:Bumetanide; D018118:Chloride Channels; D002712:Chlorides; D007192:Indenes; D009419:Nerve Tissue Proteins; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C095651:((2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy)acetic acid
keywords: H-reflex; KCC2; NKCC1; complete transection; exercise; spinal cord injury