ATP utilization in the outer retina: cones are much more expensive than rods

Abstract

Purpose : We do not know why cones are ultimately lost in progressive blinding diseases such as RP and Leber's when the initial insult is specific to the rods. Several clues suggest that cones eventually die from a lack of metabolic energy. Cone degeneration is preceded by changes in the insulin/mTOR pathway, and degeneration can be delayed by increasing glucose uptake. These observations pose the following question: Are cones especially sensitive to decreases in glucose uptake because they normally require an elevated rate of ATP consumption?

Methods : Patch-clamp recordings were made from Cx36^-/- rods and cones in retinal slices with techniques previously described. We recorded current and voltage responses to steady light across physiological light intensities. We measured synaptic calcium currents and the hyperpolarization-activated HCN conductance (i_h). Using our measurements, we calculated and compared directly the ATP demand of rods and cones. Next we used published topography measurements from primate and mouse retinas to calculate how cell density concentrates metabolic demand in these retinas.

Results : We calculated the ATP consumption in rods and cones required to balance cations entering through light-sensitive channels in the outer segment, sodium entering through i_h, and calcium entering the synaptic terminals. We also considered the synthesis of cGMP by guanylyl cyclase and other metabolic demands of phototransduction. Cones consume almost 2-fold more ATP in the dark than rods. Light suppresses the ATP demand in both cell types, but the demand in rods is suppressed with less light and to a greater extent than in cones. The predominance of rods in mouse and primates is responsible for the majority of ATP use in outer retina, but in the primate fovea the concentration of cones produces a localized spike of ATP use, even in bright daylight.

Conclusions : Cones are metabolically more expensive than rods, and they remain so even in bright light. Nevertheless, the large population of rods in most mammalian retinas continues to be the dominant energy expense even in bright light. In primates including humans, the fovea produces an intense and relatively constant ATP sink at all light levels, which may increase cone vulnerability to metabolic insult.

This is a 2020 ARVO Annual Meeting abstract.