| The K+-Cl- co-transporter 2 (KCC2) serves as the main exclusion force of Cl- in matured neurons to sustain a low intracellular Cl- concentration, which is the basis for normal GAB A inhibition. Previous studies have shown a functional decline of type A γ-aminobutyric acid receptors (GABAARs) in pathological conditions such as epilepsy, stroke or neuropathic pain. Further researches either on KCC2 or on GABAA receptor respectively have brought us the sight that both of the two suffer a loss of surface expression in an activity-dependent way, but rather few took an overall view about their correlation under same pathological conditions. Some recent studies reported that beyond exclusion of Cl- and K+, KCC2 also acts as a structural protein promoting excitatory synapse formation during maturation, which does not depend on its co-transportation. It reminds us the possibility of structural coupling between KCC2 and GABAA receptors. Here, we show that enhanced activity in rat hippocampus slices induced a down-regulation of surface KCC2 and a depolarizing shift of EGABA. The loss of surface GABAA receptor and the reduction of mIPSCs amplitude were also observed. Further analysis on epileptogenesis process indicated that the functional decline of KCC2 and GABAA receptor occurs earlier than the occurance of epilepic seizure. In addition, EEG recording and immunoblotting in seizure rats of different level revealed that down-regulation of KCC2 and GABAA receptor were co-related with burst like activities. Finally, an interaction between GABAA receptor and KCC2 was revealed by using a immunoprecipitation method. These findings indicate that the impact of KCC2 on GABA signaling, in addition to its Cl- extrusion property, also includes on their structural coupling, which may help to explain their co- regulation in activity. Adding together, the declined GABAergic inhibition may act as an important promoting factor in the process of epilepsy. |
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