Modulation of cone photoreceptor function by autophagy

ABSTRACT Autophagy is a lysosomal degradation pathway that maintains cellular homeostasis under basal and stress conditions by catabolizing cellular constituents to produce energy and building blocks. Although autophagy is common to all eukaryotic cells, highly specialized cells exploit this pathway to support their unique physiological functions. One such example is cone photoreceptors, where autophagy promotes survival during periods of metabolic or light-induced stress. The function of cones as our daytime photoreceptors depends critically on the rapid recovery of their sensitivity after exposure to bright light, a process known as dark adaptation. This metabolically-demanding process is driven by the turnover of chromophore for the regeneration of cone visual pigment and by the resetting of the efficiency of synaptic transmission between cones and cone bipolar cells. As autophagy is intimately involved in cellular metabolism, we will test the novel hypothesis that autophagy modulates the cone-driven photopic dark adaptation. We will perform experiments to determine the physiological conditions that activate autophagy in cones, focusing on bright light exposure, fasting, and physical exercise. We will also determine the subcellular compartments in cones where autophagy is upregulated in response to a range of stress conditions. To investigate the role of autophagy in cone-driven photopic dark adaptation, we will perform electrophysiological experiments to determine how fasting, exercise, or genetic block of autophagy affect the recovery of photopic function following exposure to bright light. Finally, we will evaluate two alternative mechanisms by which autophagy could be modulating photopic dark adaptation, either by accelerating the turnover of visual chromophore or by enhancing synaptic transmission. These experiments will establish autophagy as a novel mechanism for regulating the function of mammalian cone photoreceptors and photopic vision. They will also pave the way for future translational studies with humans seeking to prevent vision loss and enhance photopic vision by intermittent fasting or exercise.