Non-canonical type 1 cannabinoid receptor signaling regulates night visual processing in the inner rat retina

Type 1 cannabinoid receptors (CB1Rs) are expressed in major retinal neurons within the rod-pathway suggesting a role in regulating night visual processing, but the underlying mechanisms remain poorly understood. Using acute rat retinal slices, we show that CB1R activation reduces glutamate release from rod bipolar cell (RBC) axon terminals onto AII and A17 amacrine cells through a pathway that requires exchange proteins directly activated by cAMP (EPAC1/2) signaling. Consequently, CB1R activation abrogates reciprocal GABAergic feedback inhibition from A17 amacrine cells. Moreover, the activation of CB1Rs in vivo enhances and prolongs the time course of the dim-light rod-driven visual responses, an effect that was eliminated when both GABAA and GABAC receptors were blocked. Altogether, our findings underscore a non-canonical mechanism by which cannabinoid signaling regulates RBC dyad synapses in the inner retina to regulate dim-light visual responses to fine-tune night vision. [Display omitted] •CB1 receptors (CB1Rs) are expressed in mammalian retinal rod bipolar cells (RBCs)•In RBC, the activation of CB1R decreases glutamate release via the cAMP-EPAC pathway•By reducing glutamate release, CB1R ablate reciprocal inhibitory signal onto RBC•CB1R also modulates rod-driven light responses in vivo to fine-tune night vision Neuroscience; Molecular neuroscience; Sensory neuroscience