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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zhang, L. & McBain, C.J. Potassium conductances underlying repolarization and afterhyperpolarization in rat CA1 hippocampal interneurons. J. Physiol. (Lond.) 488, 661–672 (1995).
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).
Lorenzon, N.M. & Foehring, R.C. Relationship between repetitive firing and afterhyperpolarizations in human neocortical neurons. J. Neurophysiol. 67, 350–363 (1992).
Stackman, R.W. et al. Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J. Neurosci. 22, 10163–10171 (2002).
Habermann, E. Apamin. Pharmacol. Ther. 25, 255–270 (1984).
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).
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).
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).
Artola, A. & Singer, W. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation. Trends Neurosci. 16, 480–487 (1993).
Bliss, T.V. & Collingridge, G.L. A synaptic model of memory long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
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).
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).
Sabatini, B.L., Oertner, T.G. & Svoboda, K. The life cycle of Ca2+ ions in dendritic spines. Neuron 33, 439–452 (2002).
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).
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).
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).
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).
Katz, B. & Miledi, R. The role of calcium in neuromuscular facilitation. J. Physiol. (Lond.) 195, 481–492 (1968).
Carter, A.G. & Sabatini, B.L. State-dependent calcium signaling in dendritic spines of striatal medium spiny neurons. Neuron 44, 483–493 (2004).
Matsuzaki, M. et al. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 4, 1086–1092 (2001).
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).
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).
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).
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).
Popescu, G., Robert, A., Howe, J.R. & Auerbach, A. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004).
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).
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).
Sabatini, B.L. & Svoboda, K. Analysis of calcium channels in single spines using optical fluctuation analysis. Nature 408, 589–593 (2000).
Yasuda, R., Sabatini, B.L. & Svoboda, K. Plasticity of calcium channels in dendritic spines. Nat. Neurosci. 6, 948–955 (2003).
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).
Xia, X-M. et al. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395, 503–507 (1998).
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).
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).
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).
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).
Shah, M.M. & Haylett, D.G.K. + currents generated by NMDA receptor activation in rat hippocampal pyramidal neurons. J. Neurophysiol. 87, 2983–2989 (2002).
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).
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).
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).
Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).
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).
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).
Pologruto, T.A., Sabatini, B.L. & Svoboda, K. ScanImage: flexible software for operating laser scanning microscopes. Biomed. Eng. Online 2, 13 (2003).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1449
This article is cited by
-
BK channels sustain neuronal Ca2+ oscillations to support hippocampal long-term potentiation and memory formation
Cellular and Molecular Life Sciences (2023)
-
Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain
Nature Communications (2022)
-
Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity
Neuropsychopharmacology (2022)
-
Antidepressant activity of pharmacological and genetic deactivation of the small-conductance calcium-activated potassium channel subtype-3
Psychopharmacology (2022)
-
Elucidating the role of hypoxia/reoxygenation in hippocampus-dependent memory impairment: do SK channels play role?
Experimental Brain Research (2021)