Architecture of cannabinoid signaling in mouse retina

Cannabinoid receptors and their ligands constitute an endogenous signaling system that is found throughout the body, including the eye. This system can be activated by Δ⁹-tetrahydrocannabinol, a major drug of abuse. Cannabinoids offer considerable therapeutic potential in modulating ocular immune and inflammatory responses and in regulating intraocular pressure. The location of cannabinoid receptor 1 (cB₁) in the retina is known, but recently a constellation of proteins has been identified that produce and break down endocannabinoids (eCBs) and modulate CB₁ function. Localization of these proteins is critical to defining specific cannabinoid signaling circuitry in the retina. Here we show the localization of diacylglycerol lipase-α and -β (DGLα/β), implicated in the production of the eCB 2-arachidonoyl glycerol (2-AG); monoacylglycerol lipase (MGL) and α/β-hydrolase domain 6 (ABHD6), both implicated in the breakdown of 2-AG; cannabinoid receptor-interacting protein 1a (CRIP1a), a protein that may modulate CB₁ function; and fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase (NAAA), which have been shown to break down the eCB anandamide and related acyl amides. Our most prominent finding was that DGLα is present in postsynaptic type 1 OFF cone bipolar cells juxtaposed to CB₁-containing cone photoreceptor terminals. CRIP1a is reliably presynaptic to DGLα, consistent with a possible role in cannabinoid signaling, and NAAA is restricted to retinal pigment epithelium, whereas DGLβ is limited to retinal blood vessels. These results taken together with previous anatomical and functional studies define specific cannabinoid circuitry likely to modulate eCB signaling at the first synapse of the retina as well as in the inner plexiform layer.