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SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala

Abstract

At glutamatergic synapses, calcium influx through NMDA receptors (NMDARs) is required for long-term potentiation (LTP); this is a proposed cellular mechanism underlying memory and learning. Here we show that in lateral amygdala pyramidal neurons, SK channels are also activated by calcium influx through synaptically activated NMDARs, resulting in depression of the synaptic potential. Thus, blockade of SK channels by apamin potentiates fast glutamatergic synaptic potentials. This potentiation is blocked by the NMDAR antagonist AP5 (D(-)-2-amino-5-phosphono-valeric acid) or by buffering cytosolic calcium with BAPTA. Blockade of SK channels greatly enhances LTP of cortical inputs to lateral amygdala pyramidal neurons. These results show that NMDARs and SK channels are colocalized at glutamatergic synapses in the lateral amygdala. Calcium influx through NMDARs activates SK channels and shunts the resultant excitatory postsynaptic potential. These results demonstrate a new role for SK channels as postsynaptic regulators of synaptic efficacy.

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Figure 1: NMDARs activate SK channels that contribute to the synaptic potential.
Figure 2: EPSP amplification requires an increase in postsynaptic calcium concentration and activation of postsynaptic potassium channels.
Figure 3: Calcium influx through NMDARs activates SK channels.
Figure 4: Calcium influx through postsynaptic NMDARs activates SK channels.
Figure 5: SK channel activation follows the time course of calcium influx through NMDARs.
Figure 6: Blockade of SK channels potentiates LTP.

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References

  1. 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 

  2. Johnston, D. et al. Active dendrites, potassium channels and synaptic plasticity. Phil. Trans. R. Soc. Lond. B 358, 667–674 (2003).

    Article  CAS  Google Scholar 

  3. Tsay, D. & Yuste, R. On the electrical function of dendritic spines. Trends Neurosci. 27, 77–83 (2004).

    Article  CAS  Google Scholar 

  4. Sah, P. & Faber, E.S.L. Channels underlying neuronal calcium-activated potassium currents. Prog. Neurobiol. 66, 345–353 (2002).

    Article  CAS  Google Scholar 

  5. Stocker, M. & Pedarzani, P. Differential distributions of three Ca2+-activated K+ channel subunits, SK1, Sk2 and SK3 in the adult rat central nervous system. Mol. Cell. Neurosci. 15, 476–493 (2000).

    Article  CAS  Google Scholar 

  6. Sailer, C.A. et al. Regional differences in distribution and functional expression of small-conductance Ca2+-activated K+ channels in rat brain. J. Neurosci. 22, 9698–9707 (2002).

    Article  CAS  Google Scholar 

  7. Romey, G., Hugues, M., Schmid-Antomarchi, H. & Lazdunski, M. Apamin: a specific toxin to study a class of Ca2+-dependent K+ channels. J. Physiol. (Paris) 79, 259–264 (1984).

    CAS  Google Scholar 

  8. Castle, N.A., Haylett, D.G. & Jenkinson, D.H. Toxins in the characterization of potassium channels. Trends Neurosci. 12, 59–65 (1989).

    Article  CAS  Google Scholar 

  9. Villalobos, C., Shakkottai, V.G., Chandy, K.G., Michelhaugh, S.K. & Andrade, R. SKCa channels mediate the medium but not the slow calcium-activated afterhyperpolarization in cortical neurons. J. Neurosci. 24, 3537–3542 (2004).

    Article  CAS  Google Scholar 

  10. 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 

  11. Pedarzani, P. et al. Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J. Biol. Chem. 276, 9762–9769 (2001).

    Article  CAS  Google Scholar 

  12. Faber, E.S.L. & Sah, P. Physiological role of calcium-activated potassium currents in the rat lateral amygdala. J. Neurosci. 22, 1618–1628 (2002).

    Article  CAS  Google Scholar 

  13. Sah, P. & Bekkers, J.M. Apical dendritic location of slow-afterhyperpolarization current in hippocampal pyramidal neurons: implications for the integration of LTP. J. Neurosci. 16, 4537–4542 (1996).

    Article  CAS  Google Scholar 

  14. 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 

  15. Cangiano, L., Wallen, P. & Grillner, S. Role of apamin-sensitive k(ca) channels for reticulospinal synaptic transmission to motoneuron and for the afterhyperpolarization. J. Neurophysiol. 88, 289–299 (2002).

    Article  CAS  Google Scholar 

  16. Yamada, S., Takechi, H., Kanchiku, I., Kita, T. & Kato, N. Small-conductance Ca2+-dependent K+ channels are the target of spike-induced Ca2+ release in a feedback regulation of pyramidal cell excitability. J. Neurophysiol. 91, 2322–2329 (2004).

    Article  CAS  Google Scholar 

  17. Fiorillo, C.D. & Williams, J.T. Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394, 78–82 (1998).

    Article  CAS  Google Scholar 

  18. Grillner, S., Wallen, P., Hill, R., Cangiano, L. & El Manira, A. Ion channels of importance for the locomotor pattern generation in the lamprey brainstem-spinal cord. J. Physiol. (Lond.) 533, 23–30 (2001).

    Article  CAS  Google Scholar 

  19. 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 

  20. 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 

  21. Faber, E.S.L., Callister, R.J. & Sah, P. Morphological and electrophysiological properties of principal neurons in the rat lateral amygdala in vitro. J. Neurophysiol. 85, 714–723 (2001).

    Article  CAS  Google Scholar 

  22. Mahanty, N.K. & Sah, P. Excitatory synaptic inputs to pyramidal neurons of the lateral amygdala. Eur. J. Neurosci. 11, 1217–1222 (1999).

    Article  CAS  Google Scholar 

  23. Weisskopf, M.G. & LeDoux, J.E. Distinct populations of NMDA receptors at subcortical and cortical inputs to principal cells of the lateral amygdala. J. Neurophysiol. 81, 930–934 (1999).

    Article  CAS  Google Scholar 

  24. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984).

    Article  CAS  Google Scholar 

  25. 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 

  26. MacDermott, A.B., Mayer, M.L., Westbrook, G.L., Smith, S.J. & Barker, J.L. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature 321, 519–522 (1986).

    Article  CAS  Google Scholar 

  27. Roncarati, R., Di Chio, M., Sava, A., Terstappen, G.C. & Fumagalli, G. Presynaptic localization of the small conductance calcium-activated potassium channel SK3 at the neuromuscular junction. Neuroscience 104, 253–262 (2001).

    Article  CAS  Google Scholar 

  28. Obermair, G.J., Kaufmann, W.A., Knaus, H.G. & Flucher, B.E. The small conductance Ca2+-activated K+ channel SK3 is localized in nerve terminals of excitatory synapses of cultured mouse hippocampal neurons. Eur. J. Neurosci. 17, 721–731 (2003).

    Article  Google Scholar 

  29. Zucker, R.S. Short term synaptic plasticity. Annu. Rev. Neurosci. 12, 13–31 (1989).

    Article  CAS  Google Scholar 

  30. Neher, E. in Calcium Electrogenesis and Neuronal Functioning (eds. Heinemann, U., Klee, U., Neher, E. & Singer, W.) 80–96 (Springer, Berlin, 1986).

    Book  Google Scholar 

  31. Power, J.M. & Sah, P. Nuclear calcium signaling evoked by cholinergic stimulation in hippocampal CA1 pyramidal neurons. J. Neurosci. 22, 3454–3462 (2002).

    Article  CAS  Google Scholar 

  32. Weisskopf, M.G., Bauer, E.P. & LeDoux, J.E. L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala. J. Neurosci. 19, 10512–10519 (1999).

    Article  CAS  Google Scholar 

  33. Huang, Y.Y. & Kandel, E.R. Postsynaptic induction and PKA-dependent expression of LTP in the lateral amygdala. Neuron 21, 169–178 (1998).

    Article  CAS  Google Scholar 

  34. 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 

  35. Wei, D.S. et al. Compartmentalized and binary behavior of terminal dendrites in hippocampal pyramidal neurons. Science 293, 2272–2275 (2001).

    Article  CAS  Google Scholar 

  36. Yuste, R. & Denk, W. Dendritic spines as basic functional units of neuronal integration. Nature 375, 682–684 (1995).

    Article  CAS  Google Scholar 

  37. Kovalchuk, Y., Eilers, J., Lisman, J. & Konnerth, A. NMDA receptor-mediated subthreshold Ca2+ signals in spines of hippocampal neurons. J. Neurosci. 20, 1791–1799 (2000).

    Article  CAS  Google Scholar 

  38. 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 

  39. Humeau, Y. et al. Dendritic spine heterogeneity determines afferent-specific Hebbian plasticity in the amygdala. Neuron 45, 119–131 (2005).

    Article  CAS  Google Scholar 

  40. Glowatzki, E. & Fuchs, P.A. Cholinergic synaptic inhibition of inner hair cells in the neonatal mammalian cochlea. Science 288, 2366–2368 (2000).

    Article  CAS  Google Scholar 

  41. Oliver, D. et al. Gating of Ca2+-activated K+ channels controls fast inhibitory synaptic transmission at auditory outer hair cells. Neuron 26, 595–601 (2000).

    Article  CAS  Google Scholar 

  42. Belcadi-Abbassi, W. & Destrade, C. Post-test apamin injection suppresses a Kamin-like effect following a learning session in mice. Neuroreport 6, 1293–1296 (1995).

    Article  CAS  Google Scholar 

  43. Ikonen, S. & Riekkinen, P., Jr. Effects of apamin on memory processing of hippocampal-lesioned mice. Eur. J. Pharmacol. 382, 151–156 (1999).

    Article  CAS  Google Scholar 

  44. Ikonen, S., Schmidt, B. & Riekkinen, P., Jr. Apamin improves spatial navigation in medial septal-lesioned mice. Eur. J. Pharmacol. 347, 13–21 (1998).

    Article  CAS  Google Scholar 

  45. van der Staay, F.J., Fanelli, R.J., Blokland, A. & Schmidt, B.H. Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in mice and rats. Neurosci. Biobehav. Rev. 23, 1087–1110 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Heath and Medical Research Council of Australia and the Australian Research Council.

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Correspondence to Pankaj Sah.

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Faber, E., Delaney, A. & Sah, P. SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala. Nat Neurosci 8, 635–641 (2005). https://doi.org/10.1038/nn1450

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