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.
- Jennifer Tsui
- Delphine Gobert
- Edward S Ruthazer
- Edward S Ruthazer
- Loïs S Miraucourt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Gary L Westbrook, Vollum Institute, United States
© 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.
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Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α-synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α-synuclein strains.
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