KCC2 reverse mode helps to clear postsynaptically released potassium at glutamatergic synapses

Extracellular potassium [K(+)](o) elevation during synaptic activity retrogradely modifies presynaptic release and astrocytic uptake of glutamate. Hence, local K(+) clearance and replenishment mechanisms are crucial regulators of glutamatergic transmission and plasticity. Based on recordings of astrocytic inward rectifier potassium current I(Kir) and K(+)-sensitive electrodes as sensors of [K(+)](o) as well as on in silico modeling, we demonstrate that the neuronal K(+)-Cl(-) co-transporter KCC2 clears local perisynaptic [K(+)](o) during synaptic excitation by operating in an activity-dependent reversed mode. In reverse mode, KCC2 replenishes K(+) in dendritic spines and complements clearance of [K(+)](o), therewith attenuating presynaptic glutamate release and shortening LTP. We thus demonstrate a physiological role of KCC2 in neuron-glial interactions and regulation of synaptic signaling and plasticity through the uptake of postsynaptically released K(+).