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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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References

  1. Zhang, L. & McBain, C.J. Potassium conductances underlying repolarization and afterhyperpolarization in rat CA1 hippocampal interneurons. J. Physiol. (Lond.) 488, 661–672 (1995).

    Article  CAS  Google Scholar 

  2. Sah, P. & Mclachlan, E.M. Ca2+-activated K+ currents underlying the afterhyperpolarization in guinea pig vagal neurons: a role for Ca2+-activated Ca2+ release. Neuron 7, 257–264 (1991).

    Article  CAS  Google Scholar 

  3. Lorenzon, N.M. & Foehring, R.C. Relationship between repetitive firing and afterhyperpolarizations in human neocortical neurons. J. Neurophysiol. 67, 350–363 (1992).

    Article  CAS  Google Scholar 

  4. Stackman, R.W. et al. Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J. Neurosci. 22, 10163–10171 (2002).

    Article  CAS  Google Scholar 

  5. Habermann, E. Apamin. Pharmacol. Ther. 25, 255–270 (1984).

    Article  CAS  Google Scholar 

  6. Lisman, J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc. Natl. Acad. Sci. USA 86, 9574–9578 (1989).

    Article  CAS  Google Scholar 

  7. Mulkey, R.M. & Malenka, R.C. Mechanisms underlying induction of homosynaptic long-term depression in area CA1 of the hippocampus. Neuron 9, 967–975 (1992).

    Article  CAS  Google Scholar 

  8. Dudek, S.M. & Bear, M.F. Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-d-aspartate receptor blockade. Proc. Natl. Acad. Sci. USA 89, 4363–4367 (1992).

    Article  CAS  Google Scholar 

  9. Artola, A. & Singer, W. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci. 16, 480–487 (1993).

    Article  CAS  Google Scholar 

  10. Bliss, T.V. & Collingridge, G.L. A synaptic model of memory long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).

    Article  CAS  Google Scholar 

  11. Cummings, J.A., Mulkey, R.M., Nicoll, R.A. & Malenka, R.C. Ca2+ signaling requirements for long term depression in the hippocampus. Neuron 16, 825–833 (1996).

    Article  CAS  Google Scholar 

  12. Yang, S.N., Tang, Y.G. & Zucker, R.S. Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J. Neurophysiol. 81, 781–787 (1999).

    Article  CAS  Google Scholar 

  13. Sabatini, B.L., Oertner, T.G. & Svoboda, K. The life cycle of Ca2+ ions in dendritic spines. Neuron 33, 439–452 (2002).

    Article  CAS  Google Scholar 

  14. Mayer, M.L., Westbrook, G.L. & Guthrie, P.B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263 (1984).

    Article  CAS  Google Scholar 

  15. Lee, W.S., Ngo-Anh, T.J., Bruening-Wright, A., Maylie, J. & Adelman, J.P. Small conductance Ca2+-activated K+ channels and calmodulin: cell surface expression and gating. J. Biol. Chem. 278, 25940–25946 (2003).

    Article  CAS  Google Scholar 

  16. Ishii, T.M., Maylie, J. & Adelman, J.P. Determinants of apamin and D-tubocurarine block in SK potassium channels. J. Biol. Chem. 272, 23195–23200 (1997).

    Article  CAS  Google Scholar 

  17. Behnisch, T. & Reymann, K.G. Inhibition of apamin-sensitive calcium dependent potassium channels facilitate the induction of long-term potentiation in the CA1 region of rat hippocampus in vitro. Neurosci. Lett. 253, 91–94 (1998).

    Article  CAS  Google Scholar 

  18. Katz, B. & Miledi, R. The role of calcium in neuromuscular facilitation. J. Physiol. (Lond.) 195, 481–492 (1968).

    Article  CAS  Google Scholar 

  19. Carter, A.G. & Sabatini, B.L. State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons. Neuron 44, 483–493 (2004).

    Article  CAS  Google Scholar 

  20. Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).

    Article  CAS  Google Scholar 

  21. Bekkers, J.M. & Stevens, C.F. NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341, 230–233 (1989).

    Article  CAS  Google Scholar 

  22. Hestrin, S., Nicoll, R.A., Perkel, D.J. & Sah, P. Analysis of excitatory synaptic action in pyramidal cells using whole-cell recording from rat hippocampal slices. J. Physiol. (Lond.) 422, 203–225 (1990).

    Article  CAS  Google Scholar 

  23. Hestrin, S., Sah, P. & Nicoll, R.A. Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices. Neuron 5, 247–253 (1990).

    Article  CAS  Google Scholar 

  24. Lester, R.A.J., Clements, J.D., Westbrook, G.L. & Jahr, C.E. Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature 346, 565–567 (1990).

    Article  CAS  Google Scholar 

  25. Popescu, G., Robert, A., Howe, J.R. & Auerbach, A. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004).

    Article  CAS  Google Scholar 

  26. Erreger, K., Dravid, S.M., Banke, T.G., Wyllie, D.J. & Traynelis, S.F. Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signaling profiles. J. Physiol. (Lond.) 563, 345–352 (2005).

    Article  CAS  Google Scholar 

  27. Kampa, B.M., Clements, J., Jonas, P. & Stuart, G.J. Kinetics of Mg2+ unblock of NMDA receptors: implications for spike-timing dependent synaptic plasticity. J. Physiol. (Lond.) 556, 337–345 (2004).

    Article  CAS  Google Scholar 

  28. Sabatini, B.L. & Svoboda, K. Analysis of calcium channels in single spines using optical fluctuation analysis. Nature 408, 589–593 (2000).

    Article  CAS  Google Scholar 

  29. Yasuda, R., Sabatini, B.L. & Svoboda, K. Plasticity of calcium channels in dendritic spines. Nat. Neurosci. 6, 948–955 (2003).

    Article  CAS  Google Scholar 

  30. Naraghi, M. & Neher, E. Linearized buffered Ca2+ diffusion in microdomains and its implications for calculation of [Ca2+] at the mouth of a calcium channel. J. Neurosci. 17, 6961–6973 (1997).

    Article  CAS  Google Scholar 

  31. Xia, X-M. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998).

    Article  CAS  Google Scholar 

  32. Hirschberg, B., Maylie, J., Adelman, J.P. & Marrion, N.V. Gating of recombinant small conductance Ca-activated K+ channels by calcium. J. Gen. Physiol. 111, 565–581 (1998).

    Article  CAS  Google Scholar 

  33. Hirschberg, B., Maylie, J., Adelman, J.P. & Marrion, N.V. Gating properties of single SK channels in hippocampal CA1 pyramidal neurons. Biophys. J. 77, 1905–1913 (1999).

    Article  CAS  Google Scholar 

  34. Marrion, N.V. & Tavalin, S.J. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Nature 395, 900–905 (1998).

    Article  CAS  Google Scholar 

  35. Zorumski, C.F., Thio, L.L., Clark, G.D. & Clifford, D.B. Calcium influx through N-methyl-D-aspartate channels activates a potassium current in postnatal rat hippocampal neurons. Neurosci. Lett. 99, 293–299 (1989).

    Article  CAS  Google Scholar 

  36. Shah, M.M. & Haylett, D.G.K. + currents generated by NMDA receptor activation in rat hippocampal pyramidal neurons. J. Neurophysiol. 87, 2983–2989 (2002).

    Article  CAS  Google Scholar 

  37. Isaacson, J.S. & Murphy, G.J. Glutamate-mediated extrasynaptic inhibition: direct coupling of NMDA receptors to Ca2+-activated K+ channels. Neuron 31, 1027–1034 (2001).

    Article  CAS  Google Scholar 

  38. Paul, K., Keith, D.J. & Johnson, S.W. Modulation of calcium-activated potassium small conductance (SK) current in rat dopamine neurons of the ventral tegmental area. Neurosci. Lett. 348, 180–184 (2003).

    Article  CAS  Google Scholar 

  39. Bond, C.T. et al. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J. Neurosci. 24, 5301–5306 (2004).

    Article  CAS  Google Scholar 

  40. Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).

    Article  CAS  Google Scholar 

  41. Stocker, M., Krause, M. & Pedarzani, P. An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons. Proc. Natl. Acad. Sci. USA 96, 4662–4667 (1999).

    Article  CAS  Google Scholar 

  42. Goslin, K., Asmussen, H. & Banker, G. in Culturing Nerve Cells. 2nd edn. (eds. Goslin, K. & Banker, G.) 339–370 (MIT Press, Cambridge, Massachusetts, USA, 1998).

    Google Scholar 

  43. Pologruto, T.A., Sabatini, B.L. & Svoboda, K. ScanImage: flexible software for operating laser scanning microscopes. Biomed. Eng. Online 2, 13 (2003).

    Article  Google Scholar 

Download references

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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