CB1 receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination
- Albert Einstein College of Medicine, United States
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.
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UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites.UbiSite, https://doi.org/10.1038/s41594-018-0084-y.
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UniProt: the universal protein knowledgebaseUniprot, Nucleic Acids Res 46: 2699 (2018).
Article and author information
Author details
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.
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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