FIG. 7.
Chloride homeostasis and activity-based therapies. (A) Neuronal GABA receptor-initiated responses are highly dependent on chloride homeostasis. In healthy mature neurons, KCC2 maintains low intracellular Cl– concentration leading to an inflow of Cl– following GABAR activation (left). Whereas SCI decreases KCC2 expression and shifts chloride equilibrium (middle), activity-based therapies restore inhibition through an increase in KCC2 expression after SCI (right). This overall mitigates the hyperexcitability observed after SCI. (B) Rehabilitation increases KCC2 synthesis and post-translational mechanisms responsible for KCC2 trafficking to the membrane (increased insertion rate to the membrane and/or decreased internalization by endocytosis). Among the numerous regulators of KCC2 (not illustrated), BDNF contributes to activity-dependent shuttling of KCC2 to the motoneuronal membrane. The regulation of calpains by TrkB activation could contribute to decrease the proteolytic cleavage of KCC2 and alters its ability to extrude Cl–. Our results also suggest the presence of a retroactive feedback loop through which KCC2 can regulate BDNF expression and the activity-dependent decrease in the activation of the WNK1, due to higher levels of [Cl–]i that favor the activation of KCC2 and inactivation of NKCC1. BDNF, brain-derived neurotrophic factor; GABA, gamma-aminobutyric acid; SCI, spinal cord injury.