Endocannabinoid dynamics gate spike-timing dependent depression and potentiation

  1. Yihui Cui
  2. Ilya Prokin
  3. Hao Xu
  4. Bruno Delord
  5. Stephane Genet
  6. Laurent Venance
  7. Hugues Berry  Is a corresponding author
  1. College de France, France
  2. French Institute for Research in Computer Science and Automation, France
  3. University Pierre et Marie Curie, France

Abstract

Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.

Article and author information

Author details

  1. Yihui Cui

    Center for Interdisciplinary Research in Biology, College de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Ilya Prokin

    French Institute for Research in Computer Science and Automation, Villeurbanne, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Hao Xu

    Center for Interdisciplinary Research in Biology, College de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Bruno Delord

    University Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Stephane Genet

    University Pierre et Marie Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Laurent Venance

    Center for Interdisciplinary Research in Biology, College de France, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Hugues Berry

    French Institute for Research in Computer Science and Automation, Villeurbanne, France
    For correspondence
    hugues.berry@inria.fr
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were performed in accordance with local animal welfare committee (Center for Interdisciplinary Research in Biology and EU guidelines, directive 2010/63/EU).

Copyright

© 2016, Cui 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.

Metrics

  • 2,356
    views
  • 615
    downloads
  • 58
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yihui Cui
  2. Ilya Prokin
  3. Hao Xu
  4. Bruno Delord
  5. Stephane Genet
  6. Laurent Venance
  7. Hugues Berry
(2016)
Endocannabinoid dynamics gate spike-timing dependent depression and potentiation
eLife 5:e13185.
https://doi.org/10.7554/eLife.13185

Share this article

https://doi.org/10.7554/eLife.13185

Further reading

    1. Neuroscience
    Brian C Ruyle, Sarah Masud ... Jose A Morón
    Research Article

    Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.

    1. Neuroscience
    David C Williams, Amanda Chu ... Michael A McDannald
    Research Advance Updated

    Recognizing and responding to threat cues is essential to survival. Freezing is a predominant threat behavior in rats. We have recently shown that a threat cue can organize diverse behaviors beyond freezing, including locomotion (Chu et al., 2024). However, that experimental design was complex, required many sessions, and had rats receive many foot shock presentations. Moreover, the findings were descriptive. Here, we gave female and male Long Evans rats cue light illumination paired or unpaired with foot shock (eight total) in a conditioned suppression setting using a range of shock intensities (0.15, 0.25, 0.35, or 0.50 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.50 mA). We constructed comprehensive temporal ethograms by scoring 22,272 frames across 12 behavior categories in 200-ms intervals around cue light illumination. The 0.50 mA and 0.35 mA shock-paired visual cues suppressed reward seeking, rearing, and scaling, as well as light-directed rearing and light-directed scaling. These shock-paired visual cues further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Using complete ethogram data produced superior classification compared to behavior subsets, including an immobility subset featuring freezing. The results demonstrate diverse threat behaviors – in a short and simple procedure – containing sufficient information to distinguish the visual fear conditioning status of individual rats.