Transient Inward KCC2 Transport Balances Perisynaptic Potassium at Excitatory Synapses

Accumulation of extracellular potassium [K+]o during neuronal activity challenges neuronal function and, therefore, requires a tight control. Based on electrophysiological recordings of astrocytic /Kir as a sensor of [K+]o, we demonstrate that KCC2 clears perisynaptic [K+]o during synaptic excitation by transient and activity-dependent reversal of its canonical outward mode. This operational mode of KCC2 complements astrocytic clearance of [K+]o and thus contributes to an attenuation of presynaptic vesicle release and a shortening of LTP, preventing excess excitation. We thus provide experimental evidence in support of a longstanding hypothesis, ascribing an additional potential to KCC2 as a therapeutic target in CNS diseases.