K+ efflux through postsynaptic NMDA receptors suppresses local astrocytic glutamate uptake

Glutamatergic transmission prompts K+ efflux through postsynaptic NMDA receptors. K+ depolarizes local presynaptic terminals, boosting glutamate release, but whether it also affecting glutamate uptake remains unknown. Here, we find that the pharmacological blockade, or conditional knockout, of NMDA receptors suppresses the progressive use- dependent increase in the amplitude and decay time of the astrocytic glutamate transporter current (IGluT), whereas blocking the astrocytic inward-rectifying K+ channels prevents the decay time increase only. Glutamate spot-uncaging reveals that local astrocyte depolarization, rather than extracellular K+ rises on their own, reduces the amplitude and prolong the decay of IGluT. Biophysical simulations confirm that local transient elevations of extracellular K+ can inhibit local glutamate uptake in fine astrocytic processes. Optical glutamate sensor imaging and a two-pathway test relate postsynaptic K+ efflux to enhanced extrasynaptic glutamate signaling. Thus, postsynaptic K+ efflux facilitates presynaptic release while reducing local glutamate uptake.