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:

TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity

Nature Neuroscience volume 8, pages 1525–1533 (2005)Cite this article

Abstract

Synaptic plasticity involves activity-dependent trafficking of AMPA-type glutamate receptors. Numerous cytoplasmic scaffolding proteins are postulated to control AMPA receptor trafficking, but the detailed mechanisms remain unclear. Here, we show that the transmembrane AMPA receptor regulatory protein (TARP) γ-8, which is preferentially expressed in the mouse hippocampus, is important for AMPA receptor protein levels and extrasynaptic surface expression. By controlling the number of AMPA receptors, γ-8 is also important in long-term potentiation, but not long-term depression. This study establishes γ-8 as a critical protein for basal AMPA receptor expression and localization at extrasynaptic sites in the hippocampus and raises the possibility that TARP-dependent control of AMPA receptors during synapse development and plasticity may be widespread.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: γ-8 expression increases extrasynaptic but not synaptic AMPARs.
Figure 2: Targeted disruption of γ-8 decreases level of AMPAR proteins.
Figure 3: γ-8 mediates subcellular targeting of hippocampal AMPARs.
Figure 4: CA1 synaptic AMPAR-mediated responses are impaired in γ-8−/− mice.
Figure 5: CA3 synaptic AMPAR, but not KAR, responses are impaired in γ-8−/− mice.
Figure 6: Extrasynaptic AMPAR-mediated responses are severely reduced in hippocampus of γ-8−/− mice.
Figure 7: Impairment of LTP, but not LTD, in hippocampal CA1 synapses of γ-8−/− mice.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Dingledine, R., Borges, K., Bowie, D. & Traynelis, S.F. The glutamate receptor ion channels. Pharmacol. Rev. 51, 7–61 (1999).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Barry, M.F. & Ziff, E.B. Receptor trafficking and the plasticity of excitatory synapses. Curr. Opin. Neurobiol. 12, 279–286 (2002).

    Article  CAS  Google Scholar 

  8. Garner, C.C., Nash, J. & Huganir, R.L. PDZ domains in synapse assembly and signalling. Trends Cell Biol. 10, 274–280 (2000).

    Article  CAS  Google Scholar 

  9. Scannevin, R.H. & Huganir, R.L. Postsynaptic organization and regulation of excitatory synapses. Nat. Rev. Neurosci. 1, 133–141 (2000).

    Article  CAS  Google Scholar 

  10. Sheng, M. Molecular organization of the postsynaptic specialization. Proc. Natl. Acad. Sci. USA 98, 7058–7061 (2001).

    Article  CAS  Google Scholar 

  11. 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 

  12. Letts, V.A. et al. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat. Genet. 19, 340–347 (1998).

    Article  CAS  Google Scholar 

  13. Chen, L., Bao, S., Qiao, X. & Thompson, R.F. Impaired cerebellar synapse maturation in waggler, a mutant mouse with a disrupted neuronal calcium channel gamma subunit. Proc. Natl. Acad. Sci. USA 96, 12132–12137 (1999).

    Article  CAS  Google Scholar 

  14. Hashimoto, K. et al. Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J. Neurosci. 19, 6027–6036 (1999).

    Article  CAS  Google Scholar 

  15. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    Article  CAS  Google Scholar 

  16. Tomita, S. et al. Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J. Cell Biol. 161, 805–816 (2003).

    Article  CAS  Google Scholar 

  17. 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  CAS  Google Scholar 

  18. Klugbauer, N. et al. A family of gamma-like calcium channel subunits. FEBS Lett. 470, 189–197 (2000).

    Article  CAS  Google Scholar 

  19. Burgess, D.L., Gefrides, L.A., Foreman, P.J. & Noebels, J.L. A cluster of three novel Ca2+ channel gamma subunit genes on chromosome 19q13.4: evolution and expression profile of the gamma subunit gene family. Genomics 71, 339–350 (2001).

    Article  CAS  Google Scholar 

  20. Chu, P.J., Robertson, H.M. & Best, P.M. Calcium channel gamma subunits provide insights into the evolution of this gene family. Gene 280, 37–48 (2001).

    Article  CAS  Google Scholar 

  21. Hurtley, S.M. & Helenius, A. Protein oligomerization in the endoplasmic reticulum. Annu. Rev. Cell Biol. 5, 277–307 (1989).

    Article  CAS  Google Scholar 

  22. Hollmann, M., Maron, C. & Heinemann, S. N-glycosylation site tagging suggests a three transmembrane domain topology for the glutamate receptor GluR1. Neuron 13, 1331–1343 (1994).

    Article  CAS  Google Scholar 

  23. Sans, N. et al. Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway. J. Neurosci. 21, 7506–7516 (2001).

    Article  CAS  Google Scholar 

  24. 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 

  25. Castillo, P.E., Malenka, R.C. & Nicoll, R.A. Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182–186 (1997).

    Article  CAS  Google Scholar 

  26. Vignes, M. & Collingridge, G.L. The synaptic activation of kainate receptors. Nature 388, 179–182 (1997).

    Article  CAS  Google Scholar 

  27. Nicoll, R.A. & Malenka, R.C. Contrasting properties of two forms of long-term potentiation in the hippocampus. Nature 377, 115–118 (1995).

    Article  CAS  Google Scholar 

  28. Henze, D.A., Urban, N.N. & Barrionuevo, G. The multifarious hippocampal mossy fiber pathway: a review. Neuroscience 98, 407–427 (2000).

    Article  CAS  Google Scholar 

  29. Vandenberghe, W., Nicoll, R.A. & Bredt, D.S. Interaction with the unfolded protein response reveals a role for stargazin in biosynthetic AMPA receptor transport. J. Neurosci. 25, 1095–1102 (2005).

    Article  CAS  Google Scholar 

  30. Ellgaard, L. & Helenius, A. Quality control in the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol. 4, 181–191 (2003).

    Article  CAS  Google Scholar 

  31. Zerangue, N., Schwappach, B., Jan, Y.N. & Jan, L.Y. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels. Neuron 22, 537–548 (1999).

    Article  CAS  Google Scholar 

  32. Jensen, V. et al. A juvenile form of postsynaptic hippocampal long-term potentiation in mice deficient for the AMPA receptor subunit GluR-A. J. Physiol. (Lond.) 553, 843–856 (2003).

    Article  CAS  Google Scholar 

  33. Chien, A.J. et al. Roles of a membrane-localized beta subunit in the formation and targeting of functional L-type Ca2+ channels. J. Biol. Chem. 270, 30036–30044 (1995).

    Article  CAS  Google Scholar 

  34. Brice, N.L. et al. Importance of the different beta subunits in the membrane expression of the alpha1A and alpha2 calcium channel subunits: studies using a depolarization-sensitive alpha1A antibody. Eur. J. Neurosci. 9, 749–759 (1997).

    Article  CAS  Google Scholar 

  35. Bogdanov, Y. et al. Acidic motif responsible for plasma membrane association of the voltage-dependent calcium channel beta1b subunit. Eur. J. Neurosci. 12, 894–902 (2000).

    Article  CAS  Google Scholar 

  36. 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 

  37. Tomita, S., Stein, V., Stocker, T.J., Nicoll, R.A. & Bredt, D.S. Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs. Neuron 45, 269–277 (2005).

    Article  CAS  Google Scholar 

  38. 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 

  39. Catterall, W.A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000).

    Article  CAS  Google Scholar 

  40. Arikkath, J. & Campbell, K.P. Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr. Opin. Neurobiol. 13, 298–307 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Fremeau, R.T. et al. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304, 1815–1819 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y.-X. Wang for help in the immunogold studies, P. Seeburg for the GluRA−/− (GluR1−/−) mice and A. Tzingounis for discussion and reading the paper. This research was supported by grants (to D.S.B. and R.A.N) from the National Institutes of Health (NIH), the Howard Hughes Medical Institute Research Resources Program (to D.S.B.) and the Human Frontier Research Program (to D.S.B.). R.S.P. is supported by the Intramural Research Program of the NIH/NIDCD (National Institute on Deafness and Other Communication Disorders). R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvo Conte Center for Neuroscience Research. D.S.B. is an established investigator for the American Heart Association. N.R. is supported by a fellowship from the International Human Frontier Science Program Organization. K.B. and S.T. are supported by postdoctoral fellowships from NIH.

Author information

Author notes

  1. Nathalie Rouach

    Present address: Laboratory of Neuropharmacology, Collège de France, 11 place Marcelin Berthelot, 75005, Paris, France

  2. Nathalie Rouach and Keith Byrd: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, California, USA

    Nathalie Rouach, Guillermo M Elias, Hillel Adesnik, Siavash Karimzadegan, Colin Kealey & Roger A Nicoll

  2. Department of Physiology, University of California, San Francisco, 94143, California, USA

    Keith Byrd, Susumu Tomita, David S Bredt & Roger A Nicoll

  3. Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Ronald S Petralia

Authors
  1. Nathalie Rouach
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keith Byrd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ronald S Petralia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guillermo M Elias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hillel Adesnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susumu Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Siavash Karimzadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Colin Kealey
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David S Bredt
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roger A Nicoll
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roger A Nicoll.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Diagram depicting amount of GluR1 in the synaptic, extrasynaptic and cytoplasmic regions of hippocampal spines from γ-8−/− and γ-8+/+ mice. (PDF 832 kb)

Supplementary Methods (PDF 61 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rouach, N., Byrd, K., Petralia, R. et al. TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. Nat Neurosci 8, 1525–1533 (2005). https://doi.org/10.1038/nn1551

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1551

This article is cited by

Search

Advanced 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