Endocannabinoid signaling enhances visual responses through modulation of intracellular chloride levels in retinal ganglion cells

  1. Loïs S Miraucourt
  2. Jennifer Tsui
  3. Delphine Gobert
  4. Jean-François Desjardins
  5. Anne Schohl
  6. Mari Sild
  7. Perry Spratt
  8. Annie Castonguay
  9. Yves De Koninck
  10. Nicholas Marsh-Armstrong
  11. Paul W Wiseman
  12. Edward S Ruthazer  Is a corresponding author
  1. McGill University, Canada
  2. Institut universitaire en santé mentale de Québec, Canada
  3. Johns Hopkins University School of Medicine, United States
  4. University of La Verne, United States

Abstract

Type 1 cannabinoid receptors (CB1Rs) are widely expressed in the vertebrate retina but the role of endocannabinoids in vision is not fully understood. Here we identified a novel mechanism underlying a CB1R-mediated increase in retinal ganglion cell (RGC) intrinsic excitability acting through AMPK-dependent inhibition of NKCC1 activity. Clomeleon imaging and patch clamp recordings revealed that inhibition of NKCC1 downstream of CB1R activation reduces intracellular Cl- levels in RGCs, hyperpolarizing the resting membrane potential. We confirmed that such hyperpolarization enhances RGC action potential firing in response to subsequent depolarization, consistent with the increased intrinsic excitability of RGCs observed with CB1R activation. Using a dot avoidance assay in freely swimming Xenopus tadpoles we demonstrate that CB1R activation markedly improves visual contrast sensitivity under low light conditions. These results highlight a role for endocannabinoids in vision, and present a novel mechanism for cannabinoid modulation of neuronal activity through Cl- regulation.

Article and author information

Author details

  1. Loïs S Miraucourt

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4812-6342
  2. Jennifer Tsui

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Delphine Gobert

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Jean-François Desjardins

    Department of Physics, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Anne Schohl

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Mari Sild

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Perry Spratt

    Montreal Neurological Institute, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Annie Castonguay

    Institut universitaire en santé mentale de Québec, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Yves De Koninck

    Institut universitaire en santé mentale de Québec, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Nicholas Marsh-Armstrong

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Paul W Wiseman

    Department of Biology, University of La Verne, La Verne, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Edward S Ruthazer

    Montreal Neurological Institute, McGill University, Montreal, Canada
    For correspondence
    edward.ruthazer@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0452-3151

Funding

Fonds de Recherche du Québec - Santé (research chair, postdoctoral fellowship)

  • Jennifer Tsui
  • Delphine Gobert
  • Edward S Ruthazer

Canadian Institutes of Health Research (operating grants)

  • Edward S Ruthazer

Epilepsie Canada (postdoctoral award)

  • Loïs S Miraucourt

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

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Canadian Council on Animal Care. All animals were handled according to animal care committee protocols (#5071) approved by the Animal Care Committees of the Montreal Neurological Institute and McGill University.

Version history

  1. Received: March 10, 2016
  2. Accepted: August 4, 2016
  3. Accepted Manuscript published: August 8, 2016 (version 1)
  4. Version of Record published: August 16, 2016 (version 2)

Copyright

© 2016, Miraucourt 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

  • 6,423
    views
  • 670
    downloads
  • 14
    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. Loïs S Miraucourt
  2. Jennifer Tsui
  3. Delphine Gobert
  4. Jean-François Desjardins
  5. Anne Schohl
  6. Mari Sild
  7. Perry Spratt
  8. Annie Castonguay
  9. Yves De Koninck
  10. Nicholas Marsh-Armstrong
  11. Paul W Wiseman
  12. Edward S Ruthazer
(2016)
Endocannabinoid signaling enhances visual responses through modulation of intracellular chloride levels in retinal ganglion cells
eLife 5:e15932.
https://doi.org/10.7554/eLife.15932

Share this article

https://doi.org/10.7554/eLife.15932

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Maximilian Nagel, Marco Niestroj ... Marc Spehr
    Research Article

    In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health, and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex/strain-selective ‘raw’ chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal’s sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary ‘secretome’, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

    1. Neuroscience
    Kenta Abe, Yuki Kambe ... Tatsuo Sato
    Research Article

    Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.