Chloride Homeostasis and Motor Recovery after Spinal Cord Injury
Inhibitory pathways driven by GABA and glycine are impaired after SCI and this has detrimental consequences on walking ability. GABAA receptor function depends on [Cl-]i which is mainly determined by the neuronal expression of 2 cation chloride cotransporters (CCC), the inwardly directed Na+-K+-Cl- cotransporter isoform 1 (NKCC1) and the chloride-extruding K+-Cl- cotransporter isoform 2 (KCC2).
This project will define the involvement of CCCs in the impairment/recovery of persistent inward currents (PICs) and locomotion after SCI and determine if:
· CCC expression levels contribute to the development of spastic symptoms that hinder the locomotor pattern after SCI;
· The return to chloride homeostasis triggered by step-training contributes to PICs and locomotor recovery
· CCCs can be manipulated to enhance the benefits of step-training.
The pharmacological treatments currently available to treat spasticity have potentially serious side effects and can produce a deep long-lasting depression of spinal excitability that interferes with motor recovery. Using exercise as a “treatment” in combination with a direct action on CCCs would help to restore endogenous inhibition rather than actively depress excitability.
Exercise Modulates Sensory Processing through Chloride Homeostasis After SCI
A notable exception to the basic hyperpolarizing action of GABA takes place in dorsal root ganglion neurons and their intraspinal afferents, as GABA continues to exert a depolarizing action throughout adulthood. NKCC1 remains high to maintain high [Cl-]i and GABA induces a primary afferent depolarization (PAD). Chloride homeostasis has a strong potential to be involved in sensory processing in addition to shaping motor output.
During movement, the CNS is flooded with sensory information. Presynaptic inhibition is a key mechanism by which sensory noise/background is filtered before it reaches neurons through the inhibitory action of the PAD. This project will determine if:
· Presynaptic inhibition is modulated after SCI through a decrease in NKCC1 expression in proprioceptive DRG neurons and associated intraspinal terminals
· Exercise can restore presynaptic inhibition through a return to chloride homeostasis.
ACTIVITY DEPENDENT RESPIRATORY PLASTICITY FOLLOWING SPINAL CORD INJURY
This project is performed in collaboration with the laboratory of Dr Michael Lane at Drexel University. The objective is to use locomotor training to our research is now exploring how such strategies can be used to drive plasticity and recovery of breathing following cervical spinal cord injury. enhance respiratory neuroplasticity and long-term recovery of breathing following a cervical spinal cord injury.