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PKMζ maintains memories by regulating GluR2-dependent AMPA receptor trafficking

Nature Neuroscience volume 13, pages 630–634 (2010)Cite this article

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Abstract

The maintenance of long-term memory in hippocampus, neocortex and amygdala requires the persistent action of the atypical protein kinase C isoform, protein kinase Mζ (PKMζ). We found that inactivating PKMζ in the amygdala impaired fear memory in rats and that the extent of the impairment was positively correlated with a decrease in postsynaptic GluR2. Blocking the GluR2-dependent removal of postsynaptic AMPA receptors abolished the behavioral impairment caused by PKMζ inhibition and the associated decrease in postsynaptic GluR2 expression, which correlated with performance. Similarly, blocking this pathway for removal of GluR2-containing receptors from postsynaptic sites in amygdala slices prevented the reversal of long-term potentiation caused by inactivating PKMζ. Similar behavioral results were obtained in the hippocampus for unreinforced recognition memory of object location. Together, these findings indicate that PKMζ maintains long-term memory by regulating the trafficking of GluR2-containing AMPA receptors, the postsynaptic expression of which directly predicts memory retention.

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Figure 1: Blocking GluR2-dependent AMPA receptor synaptic removal prevents memory impairment induced by PKMζ inactivation.
Figure 2: Postsynaptic GluR2 levels are decreased in fear-conditioned rats after PKMζ inactivation and the levels of postsynaptic GluR2 correlate with the magnitude of freezing during memory retention.
Figure 3: Blocking GluR2-dependent AMPA receptor synaptic removal prevents the LTP impairment induced by PKMζ inactivation in BLA slices.
Figure 4: Blocking GluR2-dependent, postsynaptic AMPA receptor removal prevents the impairment of object location memory induced by PKMζ inactivation in the dorsal hippocampus.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada (K.N. and Y.T.W.), the E.W.R. Steacie Foundation (K.N.) and by US National Institutes of Health grants R01 MH53576 and MH57068 (T.C.S.). O.H. was supported by the German Research Society (Deutsche Forschungsgemeinschaft).

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Authors and Affiliations

  1. Department of Psychology, McGill University, Montreal, Quebec, Canada

    Paola Virginia Migues, Oliver Hardt, Karine Gamache & Karim Nader

  2. Brain Research Center and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Dong Chuan Wu & Yu Tian Wang

  3. Departments of Physiology and Pharmacology, and of Neurology, The Robert Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, Brooklyn, New York, USA

    Todd Charlton Sacktor

Authors
  1. Paola Virginia Migues
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  6. Yu Tian Wang
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Contributions

All of the authors contributed to the design of experiments, interpretation of results and editing of the manuscript. P.V.M. and O.H. conducted the behavioral studies. P.V.M. carried out the biochemical studies. D.C.W. conducted the electrophysiological studies. K.G. and O.H. performed the stereotaxic surgeries. P.V.M., O.H., T.C.S. and K.N. wrote the manuscript.

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Correspondence to Paola Virginia Migues.

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Migues, P., Hardt, O., Wu, D. et al. PKMζ maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci 13, 630–634 (2010). https://doi.org/10.1038/nn.2531

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