The defense is taking place in Bilbao
Supervisors: Giovanni Marsicano (Magendie) and Elena Vecino (Universidad del Pais Vasco)
Title
Roles of the CB1 receptor and the endocannabinoid system in the retina
Abstract
The retina, a sensory extension of the central nervous system, transforms light into electrical signals for visual processing, involving intricate neuronal and glial interactions. Key retinal neurons such as photoreceptors, bipolar, horizontal, amacrine, and ganglion cells, coordinate visual signal transmission, supported by Müller glia, which provide structural and metabolic aid. Retinal disorders, including glaucoma and diabetic retinopathy, cause irreversible blindness through neuronal degeneration.
The endocannabinoid system (ECS), a neuromodulatory network comprising cannabinoid receptors (CB1 and CB2), endocannabinoids, and enzymes for their synthesis and degradation, plays a pivotal role in modulating brain and body functions. In particular, the ECS is involved in retinal function and health, influencing neurotransmission, visual processing, and cellular communication. Its role in both normal physiology and pathological conditions highlights the therapeutic potential of cannabinoids in treating retinal disorders. However, the involvement of the endocannabinoid system in Müller glia, as well as the different roles of the CB1 receptor, particularly in retinal metabolism, vision dependent behaviours, and response to pathological insults, remains largely unexplored. This study investigated ECS roles in retinal function and pathology. CB1 receptors were localized predominantly in the inner and outer plexiform layers, overlapping with markers for photoreceptors, bipolar, horizontal, amacrine, and ganglion cells. Müller glia were confirmed to express all ECS components and synthesize endocannabinoids, primarily 2-arachidonoylglycerol, highlighting their role in neuron-glia communication mediated by cannabinoid signaling. Functionally, CB1 receptor activation reduced mitochondrial oxygen consumption in retinal homogenates, suggesting a regulatory role in retinal energy metabolism. In addition, behavioral tests revealed that CB1 receptors are critical for processing visual stimuli related to defensive behaviors, such as detecting looming threats, but are not required for spatial navigation or auditory-cue-driven fear responses. Finally, in pathological contexts, CB1 constitutive deletion showed no direct impact on retinal ganglion cell survival after ischemia/reperfusion injuries.
Overall, the findings underscore the ECS as integral to retinal health, with roles in synaptic modulation, metabolism, and visually evoked behaviors. The identification of Müller glia as active participants in ECS signaling broadens understanding of neuron-glia interactions. These insights open avenues for therapeutic exploration of cannabinoids in retinal diseases.
Jury
- Pedro de la Villa (University of Alcalá)
- Nagore Puente (University of the Basque Country)
- Guillaume Ferreira (University of Bordeaux)
- Frank Kirchhoff (Saaland University)
- and Stefanie Hauck (Helmholtz Zentrum München).