1. Neuroscience
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CB1 receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination

  1. Hannah R Monday
  2. Mathieu Bourdenx
  3. Bryen A Jordan
  4. Pablo E Castillo  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
Research Article
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Cite this article as: eLife 2020;9:e54812 doi: 10.7554/eLife.54812
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Abstract

Long-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB1)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that involves a protein synthesis-dependent long-lasting reduction in GABA release. We found that CB1-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB1 activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as ARPC2 and WASF1/WAVE1, and presynaptic release. Moreover, while CB1-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB1-iLTD. Thus, CB1-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.

Data availability

All data generated in this study are included in the manuscript and supporting files. Source data files are provided for Figure 2.The mass spectrometry proteomics data have been deposited to the ProteomeX change with identifier Consortium via the PRIDE [1] partner repository with the dataset identifier PXD020008 and 10.6019/PXD020008.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Hannah R Monday

    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mathieu Bourdenx

    Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bryen A Jordan

    Dominick P Purpura Department of Neuroscience, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Pablo E Castillo

    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States
    For correspondence
    pablo.castillo@einsteinmed.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9834-1801

Funding

National Institute of Mental Health (F31MH114431)

  • Hannah R Monday

National Institute of Mental Health (R01-MH081935)

  • Pablo E Castillo

National Institute on Drug Abuse (R01-DA17392)

  • Pablo E Castillo

National Institute of Neurological Disorders and Stroke (R01-NS113600)

  • Pablo E Castillo

National Institute on Aging (R01-AG039521)

  • Bryen A Jordan

Rainwater Charitable Foundation

  • Mathieu Bourdenx

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experimental procedures adhered to NIH and Albert Einstein College of Medicine Institutional Animal Care and Use Committee guidelines as approved by protocol #00001047.

Reviewing Editor

  1. Gary L Westbrook, Oregon Health and Science University, United States

Publication history

  1. Received: December 30, 2019
  2. Accepted: September 8, 2020
  3. Accepted Manuscript published: September 9, 2020 (version 1)
  4. Version of Record published: September 28, 2020 (version 2)

Copyright

© 2020, Monday et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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