Chloride Ion Transporter Kcc2 And Cerebral Ischemia

Stroke is one of the most important diseases. It also is the primary reason of paralysis. Transient cerebral ischemia induces a cascade of cellular events that eventually produce neuronal death. Among events, NMDA (N-methyl D-aspartate) receptor activation is critical for ischemia-induced cell death. But NMDA receptor antagonists fail clinical trials for stroke. Recently, more attention has been focused on changes in intracellular chloride ion (Cl~-). An alteration of intracellular Cl~- plays an important role in the regulation of apoptosis in non-neuronal cells. Changes in neuronal Cl~- concentration after oxygen-glucose deprivation of the adult hippocampal slice were also reported. Abundant KCC2 (chloride cotransporter-2) expression is responsible to a large extent for neuronal Cl~- extrusion and hence for the generation of Cl~--dependent hyperpolarizing postsynaptic currents mediated by ionotropic GABA_A. The normal hyperpolarizing action of GABA is reduced in KCC2 knockdown neurons. Moreover, in hippocampal CA1 neurons of epilepsy rats, the expression of KCC2 is downregulated via endogenous tyrosine receptor kinase B (TrkB) signaling activated by brain derived neurotrophic factor (BDNF). In addition, neuronal damage and neuropathic pain can also downregulate the expression of KCC2 and impair inhibition of GABAergic neurons.Though OGD (oxygen-glucose deprivation) makes hippocampal slices KCC2 downregulated, there are many differences between the in vivo and in vitro hippocampal tissue. It is difficult to value the effect of ischemia in vivo on KCC2 expression. Furthermore, the mechanism of KCC2 reduction after OGD remains unknown.An efficient chloride extrusion mechanism to maintain low intracellular chloride concentrations in postsynaptic neurons is required for...