Neural Network Adaptation in the Retina: Dopaminergic Signaling Mechanisms

Abstract

The initial steps of vision - the transduction and encoding of physical light stimuli into neural signals - occur in the retina, a multi-layered sheet of neurons that lines the back of the eye. Retinal dopamine (DA) acts as the principal modulatory neurotransmitter, whose signaling is driven by both light-sensitive and intrinsic circadian mechanisms. DA critically shapes retinal circuits and alters the processing of visual signals by initiating slow and sustained changes in the physiology of retinal neurons and synapses. Here, to achieve a mechanistic understanding of how DA reconfigures retinal circuits according to background illumination, we employed various mouse models, electrophysiological, psychophysical, and pharmacological techniques to answer three fundamental questions: (1) how does dopamine transporter (DAT)-mediated volume transmission contribute to retinal physiology? (2) how are the retinal dopaminergic system and overall visual function shaped by circadian perinatal photoperiod? and lastly, (3) how do DA receptors direct differential signaling pathways and influence ganglion cell function? We found that DAT-dependent anomalous dopamine efflux results in elevated retinal light-adapted responses in male mice, but not in female mice. In addition, we showed that developmental photoperiod imprints retinal function. Short, winter-like light cycles during retinal development and maturation have enduring detrimental effects on photopic retinal light responses and visual contrast sensitivity in mice, likely through developmental programming of retinal DA. Lastly, we uncovered differential effects mediated by D1 and D4 receptors on a specific functional type of retinal ganglion cells, ON-center sustained ganglion cells. These results have therefore provided a mechanistic framework for DA’s role in modulating the multiple dimensions of light-adapted vision. Overall our study supports the indispensable role of DA in high-resolution, light-adapted vision. We have elucidated key underlying cellular and network mechanisms by which DA signals shape retinal function and vision. Dynamic DA signaling is regulated by neurotransmitter reuptake, synthesis shaped by developmental light cycles, and segregated actions of receptors on the output of the retina.