D1 Dopamine receptors modulate cone ON bipolar cell Nav channels to control daily rhythms in photopic vision

摘要

In amphibians, voltage-gated sodium (Nav) channels in cone ON bipolar cells (ON-CBC) amplify cone signals in the dark and in mesopic background light. However, during light adaptation, dopamine, acting through D1 receptors (D1R), suppresses Nav channels and therefore act as a gain control mechanism. Curiously in rodents, Nav channel contributions to the ON-CBC-generated light-adapted electroretinogram (ERG) b-wave appear to exist even in fully light-adapted conditions. We sought to determine how rodent ON-CBC Nav channels are regulated by dopamine via D1R during light adaptation and during the circadian cycle. We first tested the sensitivity of Nav channels in mouse ON-CBCs to the modulation by dopamine via D1Rs. Although light-adaptation had little effect on Nav channel contributions to the b-wave, these channels were found to be modulated by D1Rs. We pharmacologically isolated the cone to ON-CBC circuit in fully light-adapted retinas to confirm these results. Retinal dopamine release following light adaptation has been previously shown to be increased in mice during circadian night. We first show that circadian fluctuations in ON-CBC function are suppressed in dark-adapted retinas, indicating that circadian fluctuations are a function of light adaptation. Secondly, we show that at night the mouse retina behaves similarly to those of frogs and salamanders with a gain control mechanism utilizing D1R modulation of Nav channels to suppress ON-CBC light responses in light-adapted conditions during circadian night. Taken together, these results suggest that circadian control of ON-CBC function contains an initial phase after approximately 18-30 h of dark adaptation, leading to substantial changes in b-wave amplitude after a relatively short time in free run which are dependent on D1R modulation of Nav channels.