SK channels and NMDA receptors form a Ca²⁺-mediated feedback loop in dendritic spines

Small-conductance Ca²⁺-activated K⁺ channels (SK channels) influence the induction of synaptic plasticity at hippocampal CA3-CA1 synapses. We find that in mice, SK channels are localized to dendritic spines, and their activity reduces the amplitude of evoked synaptic potentials in an NMDA receptor (NMDAR)-dependent manner. Using combined two-photon laser scanning microscopy and two-photon laser uncaging of glutamate, we show that SK channels regulate NMDAR-dependent Ca²⁺ influx within individual spines. SK channels are tightly coupled to synaptically activated Ca²⁺ sources, and their activity reduces the amplitude of NMDAR-dependent Ca²⁺ transients. These effects are mediated by a feedback loop within the spine head; during an excitatory postsynaptic potential (EPSP), Ca²⁺ influx opens SK channels that provide a local shunting current to reduce the EPSP and promote rapid Mg²⁺ block of the NMDAR. Thus, blocking SK channels facilitates the induction of long-term potentiation by enhancing NMDAR-dependent Ca²⁺ signals within dendritic spines.