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Mechanisms of CaMKII action in long-term potentiation

Key Points

  • The mechanisms that result in synapse-specific activation of calcium/calmodulin-dependent protein kinase II (CaMKII) have been determined.

  • CaMKII translocates to the synapse during long-term potentiation (LTP), in part owing to binding of CaMKII to the NMDA-type glutamate receptor (NMDAR).

  • One component of early LTP involves CaMKII phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit glutamate receptor 1 (GluR1), which increases the average channel conductance of AMPARs.

  • Early LTP also involves the phosphorylation of stargazin by CaMKII, which allows extrasynaptic AMPARs to bind to postsynaptic density protein 95 (PSD95), thereby anchoring more AMPARs at the synapse.

  • The molecular memory at a synapse may involve the formation of CaMKII–NMDAR complexes.

  • Late LTP involves spine and synapse growth, the underlying mechanisms of which are not known.

Abstract

Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.

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Figure 1: Synapse-specificity of the processes involved in long-term potentiation induction.
Figure 2: Role of CaMKII–NMDAR complex in long-term potentiation maintenance.
Figure 3: Role of CaMKII in AMPAR-mediated transmission during early long-term potentiation.
Figure 4: Mechanisms of expression processes by which CaMKII enhances AMPAR-mediated transmission.

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Acknowledgements

We thank P. De Koninck, W. Ross and N. Otmakhov for comments on this Review. We especially thank L. Chao for discussion about CaMKII structure and for preparing the figures for Box 1. We gratefully acknowledge the support of the Ellison Foundation, the US National Institutes of Health (grant R01 DA027807) and the 2011 Marine Biological Laboratory Research Award.

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Glossary

Two-photon glutamate uncaging

This technique involves focusing a pulsed laser beam into a solution that includes caged glutamate. The glutamate is released into the diffraction-limited volume when photolysis of the caged molecules by a two-photon excitation process occurs at the focus.

Two-photon fluorescence lifetime imaging

(2pFLIM). The fluorescence lifetime can be determined by measuring fluorescence decay (which occurs over a period of nanoseconds) after a short pulse of fluorescence excitation. Probes can be made in which the lifetime changes with the conformation of the protein, thereby providing a measure of its activation state.

Hebbian condition

The Hebb rule indicates that for long-term synaptic strengthening of excitatory synapses to occur, two conditions must be met: the presynaptic input at that synapse must be active and the postsynaptic neuron must be strongly depolarized by multiple excitatory inputs.

Calcium nanodomain

A region that extends a few tens of nanometres from a calcium-permeable channel and where calcium ions that have come through the channel are at a high concentration. Intracellular signalling is affected by the positioning of calcium sensors within the nanodomain.

Postsynaptic density

(PSD). A structure, rich in scaffolding proteins and enzymes, that is attached to the postsynaptic membrane.

CN compounds

Peptides that are derived from an endogenous protein that inhibits calcium/calmodulin-dependent protein kinase II.

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Lisman, J., Yasuda, R. & Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci 13, 169–182 (2012). https://doi.org/10.1038/nrn3192

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