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SK2 channel plasticity contributes to LTP at Schaffer collateral–CA1 synapses

Abstract

Long-term potentiation (LTP) of synaptic strength at Schaffer collateral synapses has largely been attributed to changes in the number and biophysical properties of AMPA receptors (AMPARs). Small-conductance Ca2+-activated K+ channels (SK2 channels) are functionally coupled with NMDA receptors (NMDARs) in CA1 spines such that their activity modulates the shape of excitatory postsynaptic potentials (EPSPs) and increases the threshold for induction of LTP. Here we show that LTP induction in mouse hippocampus abolishes SK2 channel activity in the potentiated synapses. This effect is due to SK2 channel internalization from the postsynaptic density (PSD) into the spine. Blocking PKA or cell dialysis with a peptide representing the C-terminal domain of SK2 that contains three known PKA phosphorylation sites blocks the internalization of SK2 channels after LTP induction. Thus the increase in AMPARs and the decrease in SK2 channels combine to produce the increased EPSP underlying LTP.

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Figure 1: Colocalization of SK2 and NR1 within the PSD of CA1 spines.
Figure 2: TBP induction of LTP abolishes SK2 channel activity.
Figure 3: NMDAR activity is necessary for loss of SK2 channel activity.
Figure 4: PKA activity is necessary for the LTP-dependent loss of SK2 channel activity.
Figure 5: PKA acts on spine SK2 channels.
Figure 6: Chemical induction of LTP abolishes SK2 channel function in a PKA-dependent manner.
Figure 7: Chemical induction of LTP results in a PKA-dependent decrease of SK2 immunoreactivity in the PSD.

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References

  1. Dragoi, G., Harris, K.D. & Buzsaki, G. Place representation within hippocampal networks is modified by long-term potentiation. Neuron 39, 843–853 (2003).

    Article  CAS  Google Scholar 

  2. Whitlock, J.R., Heynen, A.J., Shuler, M.G. & Bear, M.F. Learning induces long-term potentiation in the hippocampus. Science 313, 1093–1097 (2006).

    Article  CAS  Google Scholar 

  3. Gruart, A., Munoz, M.D. & Delgado-Garcia, J.M. Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice. J. Neurosci. 26, 1077–1087 (2006).

    Article  CAS  Google Scholar 

  4. Collingridge, G.L., Kehl, S.J. & McLennan, H. The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro. J. Physiol. (Lond.) 334, 19–31 (1983).

    Article  CAS  Google Scholar 

  5. 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 

  6. Malenka, R.C. & Nicoll, R.A. NMDA receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 16, 521–527 (1993).

    Article  CAS  Google Scholar 

  7. Benke, T.A., Luthi, A., Isaac, J.T. & Collingridge, G.L. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature 393, 793–797 (1998).

    Article  CAS  Google Scholar 

  8. Lee, H.K. et al. Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112, 631–643 (2003).

    Article  CAS  Google Scholar 

  9. Derkach, V., Barria, A. & Soderling, T.R. Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl. Acad. Sci. USA 96, 3269–3274 (1999).

    Article  CAS  Google Scholar 

  10. Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).

    Article  CAS  Google Scholar 

  11. Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).

    Article  CAS  Google Scholar 

  12. Kennedy, M.J. & Ehlers, M.D. Organelles and trafficking machinery for postsynaptic plasticity. Annu. Rev. Neurosci. 29, 325–362 (2006).

    Article  CAS  Google Scholar 

  13. Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).

    Article  CAS  Google Scholar 

  14. Esteban, J.A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat. Neurosci. 6, 136–143 (2003).

    Article  CAS  Google Scholar 

  15. Köhler, M. et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714 (1996).

    Article  Google Scholar 

  16. Ngo-Anh, T.J. et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat. Neurosci. 8, 642–649 (2005).

    Article  CAS  Google Scholar 

  17. Sailer, C.A., Kaufmann, W.A., Marksteiner, J. & Knaus, H.G. Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain. Mol. Cell. Neurosci. 26, 458–469 (2004).

    Article  CAS  Google Scholar 

  18. 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 

  19. Hammond, R.S. et al. Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J. Neurosci. 26, 1844–1853 (2006).

    Article  CAS  Google Scholar 

  20. Watanabe, M. et al. Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fibre-recipient layer) of the mouse hippocampal CA3 subfield. Eur. J. Neurosci. 10, 478–487 (1998).

    Article  CAS  Google Scholar 

  21. Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat. Rev. Neurosci. 3, 175–190 (2002).

    Article  CAS  Google Scholar 

  22. Derkach, V.A., Oh, M.C., Guire, E.S. & Soderling, T.R. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat. Rev. Neurosci. 8, 101–113 (2007).

    Article  CAS  Google Scholar 

  23. Pereda, A.E. et al. Ca2+/calmodulin-dependent kinase II mediates simultaneous enhancement of gap-junctional conductance and glutamatergic transmission. Proc. Natl. Acad. Sci. USA 95, 13272–13277 (1998).

    Article  CAS  Google Scholar 

  24. Ren, Y. et al. Regulation of surface localization of the small conductance Ca2+-activated potassium channel, SK2, through direct phosphorylation by cAMP-dependent protein kinase. J. Biol. Chem. 281, 11769–11779 (2006).

    Article  CAS  Google Scholar 

  25. Park, M., Penick, E.C., Edwards, J.G., Kauer, J.A. & Ehlers, M.D. Recycling endosomes supply AMPA receptors for LTP. Science 305, 1972–1975 (2004).

    Article  CAS  Google Scholar 

  26. Oh, M.C., Derkach, V.A., Guire, E.S. & Soderling, T.R. Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J. Biol. Chem. 281, 752–758 (2006).

    Article  CAS  Google Scholar 

  27. Passafaro, M., Piech, V. & Sheng, M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat. Neurosci. 4, 917–926 (2001).

    Article  CAS  Google Scholar 

  28. Roth-Alpermann, C., Morris, R.G., Korte, M. & Bonhoeffer, T. Homeostatic shutdown of long-term potentiation in the adult hippocampus. Proc. Natl. Acad. Sci. USA 103, 11039–11044 (2006).

    Article  CAS  Google Scholar 

  29. Hoffman, D.A., Sprengel, R. & Sakmann, B. Molecular dissection of hippocampal theta-burst pairing potentiation. Proc. Natl. Acad. Sci. USA 99, 7740–7745 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. Fan, Y. et al. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih . Nat. Neurosci. 8, 1542–1551 (2005).

    Article  CAS  Google Scholar 

  32. Kim, J., Jung, S.C., Clemens, A.M., Petralia, R.S. & Hoffman, D.A. Regulation of dendritic excitability by activity-dependent trafficking of the A-type K+ channel subunit Kv4.2 in hippocampal neurons. Neuron 54, 933–947 (2007).

    Article  CAS  Google Scholar 

  33. Xu, J., Kang, N., Jiang, L., Nedergaard, M. & Kang, J. Activity-dependent long-term potentiation of intrinsic excitability in hippocampal CA1 pyramidal neurons. J. Neurosci. 25, 1750–1760 (2005).

    Article  CAS  Google Scholar 

  34. Faber, E.S., Delaney, A.J. & Sah, P. SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala. Nat. Neurosci. 8, 635–641 (2005).

    Article  CAS  Google Scholar 

  35. 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 

  36. Bloodgood, B.L. & Sabatini, B.L. Nonlinear regulation of unitary synaptic signals by CaV2.3 voltage-sensitive calcium channels located in dendritic spines. Neuron 53, 249–260 (2007).

    Article  CAS  Google Scholar 

  37. Frick, A., Magee, J. & Johnston, D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites. Nat. Neurosci. 7, 126–135 (2004).

    Article  CAS  Google Scholar 

  38. Ehlers, M.D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).

    Article  CAS  Google Scholar 

  39. Malenka, R.C. et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340, 554–557 (1989).

    Article  CAS  Google Scholar 

  40. 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 

  41. Malenka, R.C. & Nicoll, R.A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  Google Scholar 

  42. Otmakhova, N.A. & Lisman, J.E. Contribution of Ih and GABAB to synaptically induced afterhyperpolarizations in CA1: a brake on the NMDA response. J. Neurophysiol. 92, 2027–2039 (2004).

    Article  CAS  Google Scholar 

  43. Blitzer, R.D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1943 (1998).

    Article  CAS  Google Scholar 

  44. Brown, G.P. et al. Long-term potentiation induced by theta frequency stimulation is regulated by a protein phosphatase-1-operated gate. J. Neurosci. 20, 7880–7887 (2000).

    Article  CAS  Google Scholar 

  45. Bolshakov, V.Y., Golan, H., Kandel, E.R. & Siegelbaum, S.A. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3–CA1 synapses in the hippocampus. Neuron 19, 635–651 (1997).

    Article  CAS  Google Scholar 

  46. Barco, A., Alarcon, J.M. & Kandel, E.R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell 108, 689–703 (2002).

    Article  CAS  Google Scholar 

  47. Bear, M.F. Mechanism for a sliding synaptic modification threshold. Neuron 15, 1–4 (1995).

    Article  CAS  Google Scholar 

  48. Bienenstock, E.L., Cooper, L.N. & Munro, P.W. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J. Neurosci. 2, 32–48 (1982).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank W.W. Wu and M. Ferking for helpful discussions. This work was funded by research grants from the US National Institutes of Health to J.P.A. and J.M. and from the Spanish Ministry of Education and Science (BFU-2006-01896) and Junta de Comunidades de Castilla-La Mancha (SAN-04-008-00, PAI05-040) to R.L.

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M.T.L. performed the electrophysiological experiments and R.L. performed the immuno-EM experiments. M.W. supplied SK2-specific antibody. J.P.A. and J.M. are the corresponding authors.

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Correspondence to John P Adelman or James Maylie.

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Lin, M., Luján, R., Watanabe, M. et al. SK2 channel plasticity contributes to LTP at Schaffer collateral–CA1 synapses. Nat Neurosci 11, 170–177 (2008). https://doi.org/10.1038/nn2041

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