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

Abstract

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.

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Figure 1: Live-cell immunostaining of a cultured hippocampal neuron expressing mSK2-myc (red) and cytosolic GFP (green).
Figure 2: SK channels modulate synaptically evoked EPSPs.
Figure 3: Apamin-induced EPSP increases require NMDAR activity.
Figure 4: Apamin has no effect on paired pulse facilitation.
Figure 5: Single synapse responses and NMDAR-dependent spine Ca2+ signals evoked with two-photon uncaging of glutamate.
Figure 6: Blocking SK channels with apamin increases NMDAR-mediated spine Ca2+ transients.
Figure 7: Effects of BAPTA and EGTA on the apamin-induced increase of the EPSP.

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Acknowledgements

We thank T. Tzounopoulos and C. Jahr for helpful discussions. We also thank G. Banker and S. Kaech-Petrie for assistance with hippocampal cultures. This work was supported by National Institutes of Health grants to J.M. and J.P.A., and by grants to B.L.S. from the Whitaker Foundation and the Searle Scholar's program.

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Correspondence to John P Adelman.

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Ngo-Anh, T., Bloodgood, B., Lin, M. et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat Neurosci 8, 642–649 (2005). https://doi.org/10.1038/nn1449

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