1. Neuroscience
Download icon

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
Research Article
  • Cited 7
  • Views 5,901
  • Annotations
Cite this article as: eLife 2016;5:e15932 doi: 10.7554/eLife.15932

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.

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.

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Publication 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

  • 5,901
    Page views
  • 639
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

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)

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

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

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression
    2. Neuroscience

    A transcriptomic taxonomy of Drosophila circadian neurons around the clock

    Dingbang Ma et al.
    Research Article Updated

    Many different functions are regulated by circadian rhythms, including those orchestrated by discrete clock neurons within animal brains. To comprehensively characterize and assign cell identity to the 75 pairs of Drosophila circadian neurons, we optimized a single-cell RNA sequencing method and assayed clock neuron gene expression at different times of day. The data identify at least 17 clock neuron categories with striking spatial regulation of gene expression. Transcription factor regulation is prominent and likely contributes to the robust circadian oscillation of many transcripts, including those that encode cell-surface proteins previously shown to be important for cell recognition and synapse formation during development. The many other clock-regulated genes also constitute an important resource for future mechanistic and functional studies between clock neurons and/or for temporal signaling to circuits elsewhere in the fly brain.

    1. Neuroscience

    Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

    Nathan P Achilly et al.
    Short Report

    Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

    1. Neuroscience

    Data-driven reduction of dendritic morphologies with preserved dendro-somatic responses

    Willem AM Wybo et al.
    Tools and Resources

    Dendrites shape information flow in neurons. Yet, there is little consensus on the level of spatial complexity at which they operate. Through carefully chosen parameter fits, solvable in the least-squares sense, we obtain accurate reduced compartmental models at any level of complexity. We show that (back-propagating) action potentials, Ca2+ spikes, and N-methyl-D-aspartate spikes can all be reproduced with few compartments. We also investigate whether afferent spatial connectivity motifs admit simplification by ablating targeted branches and grouping affected synapses onto the next proximal dendrite. We find that voltage in the remaining branches is reproduced if temporal conductance fluctuations stay below a limit that depends on the average difference in input resistance between the ablated branches and the next proximal dendrite. Furthermore, our methodology fits reduced models directly from experimental data, without requiring morphological reconstructions. We provide software that automatizes the simplification, eliminating a common hurdle toward including dendritic computations in network models.