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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References
Dragoi, G., Harris, K.D. & Buzsaki, G. Place representation within hippocampal networks is modified by long-term potentiation. Neuron 39, 843–853 (2003).
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).
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).
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).
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).
Malenka, R.C. & Nicoll, R.A. NMDA receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 16, 521–527 (1993).
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).
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).
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).
Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).
Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
Kennedy, M.J. & Ehlers, M.D. Organelles and trafficking machinery for postsynaptic plasticity. Annu. Rev. Neurosci. 29, 325–362 (2006).
Collingridge, G.L., Isaac, J.T. & Wang, Y.T. Receptor trafficking and synaptic plasticity. Nat. Rev. Neurosci. 5, 952–962 (2004).
Esteban, J.A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat. Neurosci. 6, 136–143 (2003).
Köhler, M. et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714 (1996).
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).
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).
Stackman, R.W. et al. Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J. Neurosci. 22, 10163–10171 (2002).
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).
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).
Lisman, J., Schulman, H. & Cline, H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat. Rev. Neurosci. 3, 175–190 (2002).
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).
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).
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).
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).
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).
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).
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).
Hoffman, D.A., Sprengel, R. & Sakmann, B. Molecular dissection of hippocampal theta-burst pairing potentiation. Proc. Natl. Acad. Sci. USA 99, 7740–7745 (2002).
Yasuda, R., Sabatini, B.L. & Svoboda, K. Plasticity of calcium channels in dendritic spines. Nat. Neurosci. 6, 948–955 (2003).
Fan, Y. et al. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih . Nat. Neurosci. 8, 1542–1551 (2005).
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).
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).
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).
Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).
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).
Frick, A., Magee, J. & Johnston, D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites. Nat. Neurosci. 7, 126–135 (2004).
Ehlers, M.D. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron 28, 511–525 (2000).
Malenka, R.C. et al. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340, 554–557 (1989).
Bliss, T.V. & Collingridge, G.L. A synaptic model of memory long-term potentiation in the hippocampus. Nature 361, 31–39 (1993).
Malenka, R.C. & Nicoll, R.A. Long-term potentiation—a decade of progress? Science 285, 1870–1874 (1999).
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).
Blitzer, R.D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1943 (1998).
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).
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).
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).
Bear, M.F. Mechanism for a sliding synaptic modification threshold. Neuron 15, 1–4 (1995).
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).
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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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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DOI: https://doi.org/10.1038/nn2041
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