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LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1

Nature Neuroscience volume 5, pages 27–33 (2002)Cite this article

Abstract

In the CA1 region of the rat hippocampus, long-term potentiation (LTP) requires the activation of NMDA receptors (NMDARs) and leads to an enhancement of AMPA receptor (AMPAR) function. In neonatal hippocampus, this increase in synaptic strength seems to be mediated by delivery of AMPARs to the synapse. Here we studied changes in surface expression of native AMPA and NMDA receptors following induction of LTP in the adult rat brain. In contrast to early postnatal rats, we find that LTP in the adult rat does not alter membrane association of AMPARs. Instead, LTP leads to rapid surface expression of NMDARs in a PKC- and Src-family-dependent manner. The present study suggests a developmental shift in the LTP-dependent trafficking of AMPA receptors. Moreover, our results indicate that insertion of NMDA receptors may be a key step in regulating synaptic plasticity.

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Figure 1: Long-term potentiation does not alter the membrane surface expression of AMPA receptor subunits in adult rat CA1.
Figure 2: Long-term potentiation enhances membrane surface expression of NMDA receptors.
Figure 3: LTP alters the subcellular distribution of NMDA but not AMPA receptors.
Figure 4: Enhanced function of NMDA receptors with LTP stimulation occurs via a PKC and Src family tyrosine kinase pathway. (a) Responses isolated in the presence of the AMPA receptor antagonist NBQX (2 μM) showed a rapid potentiation following LTP stimulation. Responses were abolished by the addition of APV.
Figure 5: LTP enhances surface expression of NMDA receptors via a PKC and Src family tyrosine kinase pathway and increases tyrosine phosphorylation of NR2A.
Figure 6: PKC activation and LTP stimulation upregulate surface expression of NR1 splice variants containing the C2 cassette.
Figure 7: Enhanced surface expression of NMDA receptor subunits occurs rapidly and persists for at least 3 h after LTP induction.

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Acknowledgements

We thank M.L. Dell'Acqua, J.F. MacDonald and A.C. Spalding for advice concerning this manuscript. D.R.G. and D.A.C. are funded by individual NRSAs from NIMH. S.J.C. is supported by an individual NRSA from NIAAA. This work was also funded by NIAAA RO1 AA09675 and NIH AG04418-17.

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Authors and Affiliations

  1. Department of Pharmacology, University of Colorado Health Science Center, 4200 E. Ninth Ave. Box C236, Denver, 80262, Colorado, USA

    D. R. Grosshans, S. J. Coultrap & M. D. Browning

  2. Medical Scientist Training Program, University of Colorado Health Science Center, 4200 E. Ninth Ave. Box C236, Denver, 80262, Colorado, USA

    D. R. Grosshans & D. A. Clayton

  3. Program in Neuroscience, University of Colorado Health Science Center, 4200 E. Ninth Ave. Box C236, Denver, 80262, Colorado, USA

    D. A. Clayton & M. D. Browning

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Correspondence to M. D. Browning.

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M.D.B. has a financial interest in Phosphoresolutions (Aurora, Colorado), a company that sells some of the NMDA antibodies used in this study.

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Grosshans, D., Clayton, D., Coultrap, S. et al. LTP leads to rapid surface expression of NMDA but not AMPA receptors in adult rat CA1. Nat Neurosci 5, 27–33 (2002). https://doi.org/10.1038/nn779

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