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

Elife. 2016 Aug 8;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.

Keywords: CB1 Receptor; NKCC1; chloride; endocannabinoid; neuroscience; retina; visual system; xenopus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Chlorides / metabolism
  • Contrast Sensitivity / physiology*
  • Endocannabinoids / metabolism*
  • Gene Expression Regulation
  • Ion Transport
  • Larva / physiology
  • Membrane Potentials / physiology
  • Molecular Imaging
  • Patch-Clamp Techniques
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism*
  • Signal Transduction
  • Solute Carrier Family 12, Member 2 / genetics
  • Solute Carrier Family 12, Member 2 / metabolism*
  • Vision, Ocular / physiology
  • Xenopus laevis / physiology

Substances

  • Chlorides
  • Endocannabinoids
  • Receptor, Cannabinoid, CB1
  • Recombinant Fusion Proteins
  • Solute Carrier Family 12, Member 2
  • clomeleon
  • AMP-Activated Protein Kinases

Grant support

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