Ca 2+ ‐independent, but voltage‐ and activity‐dependent regulation of the NMDA receptor outward K + current in mouse cortical neurons

To test the novel hypothesis that the K + efflux mediated by NMDA receptors might be regulated differently than the influx of Ca 2+ and Na + through the same receptor channels, NMDA receptor whole‐cell currents carried concurrently or individually by Ca 2+ , Na + and K + were analysed in cultured mouse cortical neurons. In contrast to the NMDA inward current carried by Ca 2+ and Na + , the NMDA receptor outward K + current or NMDA‐K current, recorded either in the presence or absence of extracellular Ca 2+ and Na + , and at different or the same membrane potentials, showed much less sensitivity to alterations in intracellular Ca 2+ concentration and underwent little rundown. In line with a selective regulation of the NMDA receptor K + permeability, the ratio of the NMDA inward/outward currents decreased, and the reversal potential of composite NMDA currents recorded in physiological solutions shifted by −8.5 mV after repeated activation of NMDA receptors. Moreover, a depolarizing pre‐pulse of a few seconds or a burst of brief depolarizing pulses selectively augmented the subsequent NMDA‐K current, but not the NMDA inward current. On the other hand, a hyperpolarizing pre‐pulse showed the opposite effect of reducing the NMDA‐K current. The voltage‐ and activity‐dependent regulation of the NMDA‐K current did not require the existence of extracellular Ca 2+ or Ca 2+ influx; it was, however, affected by the duration of the pre‐pulse and was subject to a time‐dependent decay. The burst of excitatory activity revealed a lasting upregulation of the NMDA‐K current even 5 s after termination of the pre‐pulses. Our data reveal a selective regulation of the NMDA receptor K + permeability and represent a novel model of voltage‐ and excitatory activity‐dependent plasticity at the receptor level.