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Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity

Nature Neuroscience volume 16, pages 874–883 (2013)Cite this article

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Abstract

The activity-regulated cytoskeletal protein Arc (also known as Arg3.1) is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes to both active synapses and the nucleus. Whereas its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in the expression of promyelocytic leukemia nuclear bodies, which decreases GluA1 (also called Gria1) transcription and synaptic strength. We further show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia protein expression and decreasing GluA1 transcription, ultimately downscaling synaptic strength.

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Figure 1: Arc becomes enriched in neuronal nuclei in mice after novel environment exposure.
Figure 2: Arc has two regions that regulate nuclear enrichment.
Figure 3: Arc contains an NES.
Figure 4: Activity regulates Arc nuclear import and export.
Figure 5: Nuclear Arc regulates synaptic strength.
Figure 6: Nuclear Arc regulates GluA1 transcription.
Figure 7: Arc mediates the activity-induced upregulation of PML-NBs, which decreases GluA1 transcription.
Figure 8: Arc localization to the nucleus mediates homeostatic plasticity.

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Acknowledgements

We thank R. Truant (McMaster University) for the GFP–β-gal construct, B. Henderson (University of Sydney) for the GFP-NLS-NES construct, R. Dingledine (Emory University) for the GluA1-luciferase and GluA2-luciferase constructs, P. Pandolfi (Sloan-Kettering Institute) for the eGFP-PML construct, D. Bredt (University of California San Francisco) for the eGFP-PSD95 construct, R. Everett (MRC–Universit of Glasgow Centre for Virus Research) for the PML and ICP0 construct and J. Ahn (Sungkyunkwan University School of Medicine) for the IE1 constructs. We thank members of the Finkbeiner lab, L. Jan, R. Edwards and N. Krogan for helpful suggestions and G. Howard for editorial input. E.K. was supported by a Ruth L. Kirschstein Fellowship (5 F31 MH087009). Primary support for this work was provided by the National Institute of Neurological Disease and Stroke (2 R01 NS39074), the National Institute on Aging (2 P01 AG022074) and the J. David Gladstone Institutes (S.F.), as well as the Keck Foundation (S.F.). The animal care facility was partly supported by a US National Institutes of Health Extramural Research Facilities Improvement Project (RR018928).

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Authors and Affiliations

  1. Gladstone Institutes of Neurological Disease, San Francisco, California, USA

    Erica Korb & Steven Finkbeiner

  2. Neuroscience Graduate Program, University of California, San Francisco, California, USA

    Erica Korb, Carol L Wilkinson, Kathryn L Lovero & Steven Finkbeiner

  3. Biomedical Science Program, University of California, San Francisco, California, USA

    Ryan N Delgado & Steven Finkbeiner

  4. Taube-Koret Center for Neurodegenerative Disease, Gladstone Institutes, San Francisco, California, USA

    Steven Finkbeiner

  5. Hellman Family Foundation Program in Alzheimer's Disease Research, Gladstone Institutes, San Francisco, California, USA

    Steven Finkbeiner

  6. Department of Neurology, University of California, San Francisco, California, USA

    Steven Finkbeiner

  7. Department of Physiology, University of California, San Francisco, California, USA

    Steven Finkbeiner

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Contributions

E.K. and S.F. designed the experiments. E.K. performed experiments. C.L.W. found Pat7 and created the Arc antiserum. R.N.D. contributed to luciferase assays. K.L.L. contributed to FRAP experiments. S.F. supervised the project. E.K. and S.F. wrote the manuscript.

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Correspondence to Steven Finkbeiner.

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Korb, E., Wilkinson, C., Delgado, R. et al. Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. Nat Neurosci 16, 874–883 (2013). https://doi.org/10.1038/nn.3429

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