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.

LTP requires a reserve pool of glutamate receptors independent of subunit type

Abstract

Long-term potentiation (LTP) of synaptic transmission is thought to be an important cellular mechanism underlying memory formation. A widely accepted model posits that LTP requires the cytoplasmic carboxyl tail (C-tail) of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1. To find the minimum necessary requirement of the GluA1 C-tail for LTP in mouse CA1 hippocampal pyramidal neurons, we used a single-cell molecular replacement strategy to replace all endogenous AMPA receptors with transfected subunits. In contrast to the prevailing model, we found no requirement of the GluA1 C-tail for LTP. In fact, replacement with the GluA2 subunit showed normal LTP, as did an artificially expressed kainate receptor not normally found at these synapses. The only conditions under which LTP was impaired were those with markedly decreased AMPA receptor surface expression, indicating a requirement for a reserve pool of receptors. These results demonstrate the synapse’s remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The role of the GluA1 C-tail in surface trafficking.
Figure 2: GluA1(ΔC) has normal synaptic targeting.
Figure 3: LTP requires no single portion of the GluA1 C-tail.
Figure 4: GluA2(Q) is sufficient to express LTP.
Figure 5: Lack of surface expression corresponds with loss of LTP in GluA1 conditional knockouts, and GluA1(ΔC) and GluA2((Q)ΔC) replacement neurons.
Figure 6: GluK1 expresses on the neuronal surface, targets to synapses and mediates LTP.

References

  1. Hollmann, M. & Heinemann, S. Cloned glutamate receptors. Annu. Rev. Neurosci. 17, 31–108 (1994)

    Article  CAS  Google Scholar 

  2. Wisden, W. & Seeburg, P. H. Mammalian ionotropic glutamate receptors. Curr. Opin. Neurobiol. 3, 291–298 (1993)

    Article  CAS  Google Scholar 

  3. Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254–268 (2009)

    Article  CAS  Google Scholar 

  4. Wenthold, R. J., Petralia, R. S., Blahos, J., II & Niedzielski, A. S. Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J. Neurosci. 16, 1982–1989 (1996)

    Article  CAS  Google Scholar 

  5. Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001)

    Article  CAS  Google Scholar 

  6. Boehm, J. et al. Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 51, 213–225 (2006)

    Article  CAS  Google Scholar 

  7. Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999)

    Article  CAS  Google Scholar 

  9. Meng, Y., Zhang, Y. & Jia, Z. Synaptic transmission and plasticity in the absence of AMPA glutamate receptor GluR2 and GluR3. Neuron 39, 163–176 (2003)

    Article  CAS  Google Scholar 

  10. Kessels, H. W. & Malinow, R. Synaptic AMPA receptor plasticity and behavior. Neuron 61, 340–350 (2009)

    Article  CAS  Google Scholar 

  11. Anggono, V. & Huganir, R. L. Regulation of AMPA receptor trafficking and synaptic plasticity. Curr. Opin. Neurobiol. 22, 461–469 (2012)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Malenka, R. C. Synaptic plasticity and AMPA receptor trafficking. Ann. NY Acad. Sci. 1003, 1–11 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Malinow, R. & Malenka, R. C. AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25, 103–126 (2002)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Shepherd, J. D. & Huganir, R. L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613–643 (2007)

    Article  CAS  Google Scholar 

  18. Granger, A. J., Gray, J. A., Lu, W. & Nicoll, R. A. Genetic analysis of neuronal ionotropic glutamate receptor subunits. J. Physiol. (Lond.) 589, 4095–4101 (2011)

    Article  CAS  Google Scholar 

  19. Lu, W., Isozaki, K., Roche, K. W. & Nicoll, R. A. Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1. Proc. Natl Acad. Sci. USA 107, 22266–22271 (2010)

    Article  ADS  CAS  Google Scholar 

  20. Andrasfalvy, B. K., Smith, M. A., Borchardt, T., Sprengel, R. & Magee, J. C. Impaired regulation of synaptic strength in hippocampal neurons from GluR1-deficient mice. J. Physiol. (Lond.) 552, 35–45 (2003)

    Article  CAS  Google Scholar 

  21. Panicker, S., Brown, K. & Nicoll, R. A. Synaptic AMPA receptor subunit trafficking is independent of the C terminus in the GluR2-lacking mouse. Proc. Natl Acad. Sci. USA 105, 1032–1037 (2008)

    Article  ADS  CAS  Google Scholar 

  22. Shen, L., Liang, F., Walensky, L. D. & Huganir, R. L. Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association. J. Neurosci. 20, 7932–7940 (2000)

    Article  CAS  Google Scholar 

  23. Coleman, S. K., Cai, C., Mottershead, D. G., Haapalahti, J. P. & Keinanen, K. Surface expression of GluR-D AMPA receptor is dependent on an interaction between its C-terminal domain and a 4.1 protein. J. Neurosci. 23, 798–806 (2003)

    Article  CAS  Google Scholar 

  24. Jackson, A. C. & Nicoll, R. A. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199 (2011)

    Article  CAS  Google Scholar 

  25. Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005)

    Article  ADS  CAS  Google Scholar 

  26. Lin, D. T. et al. Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nature Neurosci. 12, 879–887 (2009)

    Article  CAS  Google Scholar 

  27. Greger, I. H., Ziff, E. B. & Penn, A. C. Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci. 30, 407–416 (2007)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Zhang, W. et al. A transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61, 385–396 (2009)

    Article  CAS  Google Scholar 

  30. Copits, B. A., Robbins, J. S., Frausto, S. & Swanson, G. T. Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins. J. Neurosci. 31, 7334–7340 (2011)

    Article  CAS  Google Scholar 

  31. Dargan, S. L. et al. ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function. Neuropharmacology 56, 121–130 (2009)

    Article  CAS  Google Scholar 

  32. 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 

  33. Makino, Y., Johnson, R. C., Yu. Y, Takamiya K & Huganir R .L Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor. Proc. Natl Acad. Sci. USA 108, 8450–8455 (2011)

    Article  ADS  CAS  Google Scholar 

  34. Lisman, J., Yasuda, R. & Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nature Rev. Neurosci. 13, 169–182 (2012)

    Article  CAS  Google Scholar 

  35. Opazo, P. & Choquet, D. A three-step model for the synaptic recruitment of AMPA receptors. Mol. Cell. Neurosci. 46, 1–8 (2011)

    Article  CAS  Google Scholar 

  36. Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. & Kasai, H. Structural basis of long-term potentiation in single dendritic spines. Nature 429, 761–766 (2004)

    Article  ADS  CAS  Google Scholar 

  37. Murakoshi, H. & Yasuda, R. Postsynaptic signaling during plasticity of dendritic spines. Trends Neurosci. 35, 135–143 (2012)

    Article  CAS  Google Scholar 

  38. Patterson, M. & Yasuda, R. Signalling pathways underlying structural plasticity of dendritic spines. Br. J. Pharmacol. 163, 1626–1638 (2011)

    Article  CAS  Google Scholar 

  39. Stoppini, L., Buchs, P. A. & Muller, D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182 (1991)

    Article  CAS  Google Scholar 

  40. Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002)

    Article  ADS  CAS  Google Scholar 

  41. Elias, G. M., Elias, L. A., Apostolides, P. F., Kriegstein, A. R. & Nicoll, R. A. Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development. Proc. Natl Acad. Sci. USA 105, 20953–20958 (2008)

    Article  ADS  CAS  Google Scholar 

  42. Navarro-Quiroga, I., Chittajallu, R., Gallo, V. & Haydar, T. F. Long-term, selective gene expression in developing and adult hippocampal pyramidal neurons using focal in utero electroporation. J. Neurosci. 27, 5007–5011 (2007)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Jackson, J. Levy, S. Fischbach, K. Lovero, N. Sheng, S. Shipman and M. Younger for critical discussions and reading of the manuscript; K. Bjorgen for technical help with organotypic slice cultures; and L. Subramanian from the Kriegstein laboratory for technical help with in utero electroporations. We thank P. Seeburg and R. Sprengel for the Gria1–3fl/fl mice. A.J.G. was supported by the National Science Foundation Graduate Research Fellowship. R.A.N. is supported by the National Institute of Health.

Author information

Authors and Affiliations

Authors

Contributions

M.C. carried out electroporations and maintained Gria1–3fl/fl mice. Y.S. collected GluK1 overexpression data. W.L. was involved in study design and cloned several constructs. A.J.G. designed the study, collected and analysed data, and wrote the paper. R.A.N. conceived the study, contributed to the design of experiments and wrote the paper. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Roger A. Nicoll.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary Methods, Supplementary Figures 1-9 and Supplementary References. (PDF 792 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Granger, A., Shi, Y., Lu, W. et al. LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493, 495–500 (2013). https://doi.org/10.1038/nature11775

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11775

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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