Cnr2 is important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors

Abstract

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva

Cannabinoid Signaling in Auditory Function and Development

“…However, a recent study in the developing (3-day post-fertilization) zebrafish has shown that Cnr2 is expressed in both the sensory epithelia (SE) of the inner ear and lateral line neuromast. Loss of function of the cnr2 gene resulted in the formation of immature synapses and irregular tethering of ribbons as well as changes in size, shape, and number of the neurotransmitter containing vesicles and resulted in accelerated vesicular trafficking (Colon-Cruz et al, 2020). So far, it remains unknown, whether CB2 activation plays similar roles in rodents or other mammals, but the study is suggestive that ECB signaling could play a critical role in the establishment and maintenance of ribbon synapses in cochlear IHCs.…”