CB1 receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination
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.
Reviewing Editor
- Gary L Westbrook, Oregon Health and Science University, United States
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.
Version history
- Received: December 30, 2019
- Accepted: September 8, 2020
- Accepted Manuscript published: September 9, 2020 (version 1)
- 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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Further reading
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Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or ‘iconic’ memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.
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- Neuroscience
Our ability to recall details from a remembered image depends on a single mechanism that is engaged from the very moment the image disappears from view.