Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation

This article has been updated

Abstract

Long-term potentiation (LTP) in the rat hippocampus is the most extensively studied cellular model for learning and memory. Induction of classical LTP involves an NMDA-receptor- and calcium-dependent increase in functional synaptic AMPA receptors, mediated by enhanced recycling of internalized AMPA receptors back to the postsynaptic membrane. Here we report a physiologically relevant NMDA-receptor-independent mechanism that drives increased AMPA receptor recycling and LTP. This pathway requires the metabotropic action of kainate receptors and activation of G protein, protein kinase C and phospholipase C. Like classical LTP, kainate-receptor-dependent LTP recruits recycling endosomes to spines, enhances synaptic recycling of AMPA receptors to increase their surface expression and elicits structural changes in spines, including increased growth and maturation. These data reveal a new and, to our knowledge, previously unsuspected role for postsynaptic kainate receptors in the induction of functional and structural plasticity in the hippocampus.

This is a preview of subscription content, access via your institution

Access options

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

Figure 1: KA increases AMPAR surface expression.
Figure 2: KAR activation induces LTP.
Figure 3: KAR LTP induces structural plasticity.
Figure 4: KAR LTP recruits Rab11-recycling endosomes to spines.
Figure 5: KAR LTP requires intracellular calcium increase, as well as PKC and PLC activation.
Figure 6: KAR LTP requires KAR metabotropic signaling.
Figure 7: KAR LTP does not require ionotropic KAR activation.

Similar content being viewed by others

Change history

  • 08 March 2017

    In the version of this article initially published online, the graph in the second row of Figure 5c was a duplicate of the one in the first row. Also, "EPSC amplitudes" in the legend to Figure 5d should have read "EPSP slopes." Finally, the units on the x axes in Figure 4c, 5c, 6f and 7d should have been μm, not mm. The errors have been corrected in the print, PDF and HTML versions of this article.

References

  1. Malenka, R.C. & Bear, M.F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    CAS  PubMed  Google Scholar 

  2. Lu, W. et al. Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron 29, 243–254 (2001).

    CAS  PubMed  Google Scholar 

  3. 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).

    CAS  PubMed  Google Scholar 

  4. Park, M. et al. Plasticity-induced growth of dendritic spines by exocytic trafficking from recycling endosomes. Neuron 52, 817–830 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Contractor, A., Mulle, C. & Swanson, G.T. Kainate receptors coming of age: milestones of two decades of research. Trends Neurosci. 34, 154–163 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lerma, J. & Marques, J.M. Kainate receptors in health and disease. Neuron 80, 292–311 (2013).

    CAS  PubMed  Google Scholar 

  7. González-González, I.M. et al. Kainate receptor trafficking. WIRES Membrane Trasnsport and Signalling 1, 31–44 (2012).

    Google Scholar 

  8. Rodríguez-Moreno, A. & Lerma, J. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 20, 1211–1218 (1998).

    PubMed  Google Scholar 

  9. Rozas, J.L., Paternain, A.V. & Lerma, J. Noncanonical signaling by ionotropic kainate receptors. Neuron 39, 543–553 (2003).

    CAS  PubMed  Google Scholar 

  10. Rutkowska-Wlodarczyk, I. et al. A proteomic analysis reveals the interaction of GluK1 ionotropic kainate receptor subunits with Go proteins. J. Neurosci. 35, 5171–5179 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Melyan, Z., Wheal, H.V. & Lancaster, B. Metabotropic-mediated kainate receptor regulation of IsAHP and excitability in pyramidal cells. Neuron 34, 107–114 (2002).

    CAS  PubMed  Google Scholar 

  12. Fisahn, A., Heinemann, S. & McBain, C.J. The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurons. J. Physiol. 562, 199–203 (2004).

    PubMed  PubMed Central  Google Scholar 

  13. Melyan, Z., Lancaster, B. & Wheal, H.V. Metabotropic regulation of intrinsic excitability by synaptic activation of kainate receptors. J. Neurosci. 24, 4530–4534 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ruiz, A., Sachidhanandam, S., Utvik, J.K., Coussen, F. & Mulle, C. Distinct subunits in heteromeric kainate receptors mediate ionotropic and metabotropic function at hippocampal mossy fiber synapses. J. Neurosci. 25, 11710–11718 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Rivera, R., Rozas, J.L. & Lerma, J. PKC-dependent autoregulation of membrane kainate receptors. EMBO J. 26, 4359–4367 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Martin, S., Bouschet, T., Jenkins, E.L., Nishimune, A. & Henley, J.M. Bidirectional regulation of kainate receptor surface expression in hippocampal neurons. J. Biol. Chem. 283, 36435–36440 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Selak, S. et al. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. Neuron 63, 357–371 (2009).

    CAS  PubMed  Google Scholar 

  18. Carta, M. et al. CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors. EMBO J. 32, 496–510 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. González-González, I.M. & Henley, J.M. Postsynaptic kainate receptor recycling and surface expression are regulated by metabotropic autoreceptor signalling. Traffic 14, 810–822 (2013).

    PubMed  PubMed Central  Google Scholar 

  20. Bureau, I., Bischoff, S., Heinemann, S.F. & Mulle, C. Kainate receptor-mediated responses in the CA1 field of wild-type and GluR6-deficient mice. J. Neurosci. 19, 653–663 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Grover, L.M. & Teyler, T.J. N-methyl-D-aspartate receptor-independent long-term potentiation in area CA1 of rat hippocampus: input-specific induction and preclusion in a non-tetanized pathway. Neuroscience 49, 7–11 (1992).

    CAS  PubMed  Google Scholar 

  22. Grover, L.M. & Teyler, T.J. Two components of long-term potentiation induced by different patterns of afferent activation. Nature 347, 477–479 (1990).

    CAS  PubMed  Google Scholar 

  23. Behrens, C.J., van den Boom, L.P., de Hoz, L., Friedman, A. & Heinemann, U. Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks. Nat. Neurosci. 8, 1560–1567 (2005).

    CAS  PubMed  Google Scholar 

  24. Grover, L.M. Evidence for postsynaptic induction and expression of NMDA receptor independent LTP. J. Neurophysiol. 79, 1167–1182 (1998).

    CAS  PubMed  Google Scholar 

  25. Huang, Y.Y. & Malenka, R.C. Examination of TEA-induced synaptic enhancement in area CA1 of the hippocampus: the role of voltage-dependent Ca2+ channels in the induction of LTP. J. Neurosci. 13, 568–576 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Brown, T.C., Correia, S.S., Petrok, C.N. & Esteban, J.A. Functional compartmentalization of endosomal trafficking for the synaptic delivery of AMPA receptors during long-term potentiation. J. Neurosci. 27, 13311–13315 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. van Weert, A.W., Geuze, H.J., Groothuis, B. & Stoorvogel, W. Primaquine interferes with membrane recycling from endosomes to the plasma membrane through a direct interaction with endosomes which does not involve neutralisation of endosomal pH nor osmotic swelling of endosomes. Eur. J. Cell Biol. 79, 394–399 (2000).

    CAS  PubMed  Google Scholar 

  28. Mollenhauer, H.H., James Morré, D. & Rowe, L.D. Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim Biophys Acta 1031, 225–246 (1990).

    CAS  PubMed  Google Scholar 

  29. Sihra, T.S., Flores, G. & Rodriguez-Moreno, A. Kainate receptors: multiple roles in neuronal plasticity. Neuroscientist 20, 29–43 (2014).

    PubMed  Google Scholar 

  30. Lynch, G., Larson, J., Kelso, S., Barrionuevo, G. & Schottler, F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 305, 719–721 (1983).

    CAS  PubMed  Google Scholar 

  31. Malenka, R.C., Kauer, J.A., Zucker, R.S. & Nicoll, R.A. Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science 242, 81–84 (1988).

    CAS  PubMed  Google Scholar 

  32. Zong, X. & Lux, H.D. Augmentation of calcium channel currents in response to G protein activation by GTP gamma S in chick sensory neurons. J. Neurosci. 14, 4847–4853 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pinheiro, P.S. et al. Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses. Cereb. Cortex 23, 323–331 (2013).

    PubMed  Google Scholar 

  34. Marques, J.M. et al. CRMP2 tethers kainate receptor activity to cytoskeleton dynamics during neuronal maturation. J. Neurosci. 33, 18298–18310 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lanore, F. et al. Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability. J. Neurosci. 32, 17882–17893 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tashiro, A., Dunaevsky, A., Blazeski, R., Mason, C.A. & Yuste, R. Bidirectional regulation of hippocampal mossy fiber filopodial motility by kainate receptors: a two-step model of synaptogenesis. Neuron 38, 773–784 (2003).

    CAS  PubMed  Google Scholar 

  37. Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Matsuzaki, M. Factors critical for the plasticity of dendritic spines and memory storage. Neurosci. Res. 57, 1–9 (2007).

    PubMed  Google Scholar 

  40. Wang, Z. et al. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell 135, 535–548 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lerma, J. Kainate receptor physiology. Curr. Opin. Pharmacol. 6, 89–97 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Ylinen, A. et al. Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J. Neurosci. 15, 30–46 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. O'Neill, J., Senior, T. & Csicsvari, J. Place-selective firing of CA1 pyramidal cells during sharp wave/ripple network patterns in exploratory behavior. Neuron 49, 143–155 (2006).

    CAS  PubMed  Google Scholar 

  45. Ego-Stengel, V. & Wilson, M.A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20, 1–10 (2010).

    PubMed  PubMed Central  Google Scholar 

  46. Kato, H.K., Kassai, H., Watabe, A.M., Aiba, A. & Manabe, T. Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+ channel in mouse CA1 pyramidal cells. J. Physiol. (Lond.) 590, 3019–3034 (2012).

    CAS  Google Scholar 

  47. Miyazaki, K. & Ross, W.N. Ca2+ sparks and puffs are generated and interact in rat hippocampal CA1 pyramidal neuron dendrites. J. Neurosci. 33, 17777–17788 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Crépel, V. & Mulle, C. Physiopathology of kainate receptors in epilepsy. Curr. Opin. Pharmacol. 20, 83–88 (2015).

    PubMed  Google Scholar 

  49. Motazacker, M.M. et al. A defect in the ionotropic glutamate receptor 6 gene (GRIK2) is associated with autosomal recessive mental retardation. Am. J. Hum. Genet. 81, 792–798 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Petrovic, M.M. et al. Inhibition of post-synaptic Kv7/KCNQ/M channels facilitates long-term potentiation in the hippocampus. PLoS One 7, e30402 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bezanilla, F. & Armstrong, C.M. Inactivation of the sodium channel. I. Sodium current experiments. J. Gen. Physiol. 70, 549–566 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Cottrell, J.R., Borok, E., Horvath, T.L. & Nedivi, E. CPG2: a brain- and synapse-specific protein that regulates the endocytosis of glutamate receptors. Neuron 44, 677–690 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zürner, M., Mittelstaedt, T., tom Dieck, S., Becker, A. & Schoch, S. Analyses of the spatiotemporal expression and subcellular localization of liprin-α proteins. J. Comp. Neurol. 519, 3019–3039 (2011).

    PubMed  Google Scholar 

  54. King, A.E., Chung, R.S., Vickers, J.C. & Dickson, T.C. Localization of glutamate receptors in developing cortical neurons in culture and relationship to susceptibility to excitotoxicity. J. Comp. Neurol. 498, 277–294 (2006).

    CAS  PubMed  Google Scholar 

  55. Akchiche, N. et al. Differentiation and neural integration of hippocampal neuronal progenitors: signaling pathways sequentially involved. Hippocampus 20, 949–961 (2010).

    CAS  PubMed  Google Scholar 

  56. Bombeiro, A.L. et al. Correction: MHC-I and PirB upregulation in the central and peripheral nervous system following sciatic nerve injury. PLoS One 11, e0165185 (2016).

    PubMed  PubMed Central  Google Scholar 

  57. Unal, G., Joshi, A., Viney, T.J., Kis, V. & Somogyi, P. Synaptic targets of medial septal projections in the hippocampus and extrahippocampal cortices of the mouse. J. Neurosci. 35, 15812–15826 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Torigoe, M., Yamauchi, K., Zhu, Y., Kobayashi, H. & Murakami, F. Association of astrocytes with neurons and astrocytes derived from distinct progenitor domains in the subpallium. Sci. Rep. 5, 12258 (2015).

    PubMed  PubMed Central  Google Scholar 

  59. Grelli, K.N. et al. Alteration of isocitrate dehydrogenase following acute ischemic injury as a means to improve cellular energetic status in neuroadaptation. CNS Neurol. Disord. Drug Targets 12, 849–860 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Rodriguez, A., Ehlenberger, D.B., Hof, P.R. & Wearne, S.L. Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images. Nat. Protoc. 1, 2152–2161 (2006).

    CAS  PubMed  Google Scholar 

  61. Rodriguez, A., Ehlenberger, D.B., Dickstein, D.L., Hof, P.R. & Wearne, S.L. Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 3, e1997 (2008).

    PubMed  PubMed Central  Google Scholar 

  62. Bodon, G. et al. Charged multivesicular body protein 2B (CHMP2B) of the endosomal sorting complex required for transport-III (ESCRT-III) polymerizes into helical structures deforming the plasma membrane. J. Biol. Chem. 286, 40276–40286 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Chamberlain, S.E. et al. SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity. Nat. Neurosci. 15, 845–852 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gerges, N.Z., Brown, T.C., Correia, S.S. & Esteban, J.A. Analysis of Rab protein function in neurotransmitter receptor trafficking at hippocampal synapses. Methods Enzymol. 403, 153–166 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to P. Rubin and N. Grosjean for excellent technical support, A. Singh for his help in some follow-up experiments, M. Gajic for the advice about statistics and J. Esteban (CBMSO, Madrid) for providing Rab constructs. We are grateful for financial support from the ERC (Proposal no. 232881), MRC (MR/L003791), BHF (PG/14/60/31014) and BBSRC (BB/K014366 and BB/K014358) to J.M.H.; EMBO Fellowships to I.M.G.-G. (ALTF 224-2009 and ASTF 438-2011) and M.M.P. (ASTF 232-2011); a grant from MRC (MR/M023729/1) to M.M.P.; grants from the Centre National de la Recherche Scientifique, the Conseil Régional d'Aquitaine, the Labex BRAIN and the Fundacao para a Ciencia e a Tecnologia to C.M. and S.V.d.S.; support from the Czech Science Foundation (GACR): 17-02300S) and Research Project of the AS CR RVO (67985823) to L.V.; and a grant from the Department of Science and Technology (DST) – Young Scientist Scheme (SERB/LS-779/2013) to J.P.C.

Author information

Authors and Affiliations

Authors

Contributions

I.M.G.-G. designed and performed the biochemistry and imaging experiments and participated in electrophysiological experiments; M.M.P. designed and performed agonist- and stimulation-evoked electrophysiology and participated in imaging experiments. S.V.d.S. performed electrophysiology in wild-type and mice hippocampal slices; C.M. provided knockout mice and extensive advice; J.P.C. performed the MK-801, D-APV and CNQX dual pathway electrophysiological experiments. L.V. provided facilities and reagents and helped analyses the electrophysiological data. J.M.H. instigated the study and provided overall supervision and management. J.M.H., M.I.G.-G. and M.M.P. designed the study, analyzed the data and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Milos M Petrovic, Inmaculada M González-González or Jeremy M Henley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15 (PDF 3288 kb)

Supplementary Methods Checklist (PDF 1100 kb)

Supplementary Table 1

Supplementary statistical information (XLSX 23 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Petrovic, M., Viana da Silva, S., Clement, J. et al. Metabotropic action of postsynaptic kainate receptors triggers hippocampal long-term potentiation. Nat Neurosci 20, 529–539 (2017). https://doi.org/10.1038/nn.4505

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.4505

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing