Ionotropic glutamate receptors are permeable to K+ ions and therefore produce its efflux during synaptic transmission.

High postsynaptic receptor density and narrowness of synaptic cleft lead to relatively high concentrations of K+ within individual synapses.

This, however, does not significantly affect volume averaged concentration of K+ prompting its local action. We used whole cell astrocytic recordings in murine hippocampal slices to demonstrate that majority of synaptic K+ originates from activation of postsynaptic NMDA receptors.

This process was regulated by activity dependent relief of Mg2+ block of NMDA receptors. K+ concentration supralinearly increased during the trains of presynaptic stimulation or as result of pairing of synaptic stimulation and backpropagating action potential.

Significant accumulation of K+ within synaptic cleft could trigger depolarization of axonal bouton and local astrocytic processes.

This resulted in postsynaptic NMDA receptor dependent increase in presynaptic Ca2+ transients and decrease of glutamate uptake by the astrocyte.

Both could potentially lead to facilitation of the synapse and increased glutamate spillover. Moreover our findings could explain previous reports demonstrating presynaptic effects of NMDA receptor blockade.