Modulation of GABAergic transmission by activity via postsynaptic Ca ²⁺-dependent regulation of KCC2 function

Activity-induced modification of GABAergic transmission contributes to the plasticity of neural circuits. In the present work we found that prolonged postsynaptic spiking of hippocampal neurons led to a shift in the reversal potential of GABA-induced Cl^- currents (E_Cl) toward positive levels in a duration- and frequency-dependent manner. This effect was abolished by blocking cytosolic Ca²⁺ elevation and mimicked by releasing Ca²⁺ from internal stores. Activity- and Ca ²⁺-induced E_Cl shifts were larger in mature neurons, which express the K-Cl cotransporter KCC2 at high levels, and inhibition of KCC2 occluded the shifts. Overexpression of KCC2 in young cultured neurons, which express lower levels of KCC2 and have a more positive E_Cl, resulted in hyperpolarized E_Cl similar to that of mature cells. Importantly, these young KCC2-expressing neurons became responsive to neuronal spiking and Ca²⁺ elevation by showing positive E_Cl shifts. Thus, repetitive postsynaptic spiking reduces the inhibitory action of GABA through a Ca²⁺-dependent downregulation of KCC2 function.