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Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity

Nature volume 405, pages 955–959 (2000)Cite this article

Abstract

Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain1,2,3,4. LTP and LTD may be mediated by the modulation of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation5,6,7. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.

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Figure 1: Homosynaptic LTD in CA1 is associated with dephosphorylation of GluR1 at a PKA site.
Figure 2: LTP induction increases phosphorylation at CaMKII phosphorylation site on GluR1.
Figure 3: Depotentiation results in dephosphorylation of a CaMKII site on GluR1, whereas de-depression is associated with an increase in phosphorylation of a PKA site.
Figure 4: De-depression and LTP utilize different signal transduction pathways for their expression.
Figure 5: A model explaining the bidirectional changes in AMPA-receptor phosphorylation and NMDA-receptor-dependent synaptic plasticity.

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Acknowledgements

We thank C. Doherty for help in preparing the antibodies and D. Bury for help with the manuscript. This work was supported by the Howard Hughes Medical Institute, NARSAD and The Grable Foundation.

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Authors and Affiliations

  1. Howard Hughes Medical Institute Department of Neuroscience, Johns Hopkins Medical School, Baltimore , 1205, Maryland, USA

    Hey-Kyoung Lee & Richard L. Huganir

  2. Department of Neuroscience, Howard Hughes Medical Institute, Brown University, Providence, 02912, Richmond , USA

    Michaela Barbarosie & Mark F. Bear

  3. Laboratory of Molecular Neurobiology, National Institute of Bioscience and Human Technology, Ibaraki , 305-8566, Japan

    Kimihiko Kameyama

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Correspondence to Richard L. Huganir.

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Lee, HK., Barbarosie, M., Kameyama, K. et al. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000). https://doi.org/10.1038/35016089

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