Dopamine signaling and myopia development: What are the key challenges

Abstract

In the face of an "epidemic" increase in myopia over the last decades and myopia prevalence predicted to reach 2.5 billion people by the end of this decade, there is an urgent need to develop effective and safe therapeutic interventions to slow down this "myopia booming" and prevent myopia-related complications and vision loss. Dopamine (DA) is an important neurotransmitter in the retina and mediates diverse functions including retina development, visual signaling, and refractive development. Inspired by the convergence of epidemiological and animal studies in support of the inverse relationship between outdoor activity and risk of developing myopia and by the close biological relationship between light exposure and dopamine release/signaling, we felt it is timely and important to critically review the role of DA in myopia development. This review will revisit several key points of evidence for and against DA mediating light control of myopia: 1) the causal role of extracellular retinal DA levels, 2) the mechanism and action of dopamine D1 and D2 receptors and 3) the roles of cellular/circuit retinal pathways. We examine the experiments that show causation by altering DA, DA receptors and visual pathways using pharmacological, transgenic, or visual environment approaches. Furthermore, we critically evaluate the safety issues of a DA-based treatment strategy and some approaches to address these issues. The review identifies the key questions and challenges in translating basic knowledge on DA signaling and myopia from animal studies into effective pharmacological treatments for myopia in children.

Keywords: Apomorphine; D1 receptor; D2 receptor; Dopamine; Myopia.

Figure 1. A working hypothesis: Homeostatic control of myopia by opposing effects of D1-like and D2-like receptors in mouse eye

Based on genetic and pharmacological results from mouse models of myopia, we postulate that D1-like and D2-like receptor activation in distinct cell types exert homeostatic control of the emmetropization process. The balance of D1-like and D2-like receptor activation in the eye modulates refractive eye development, such that over activation of D1-like receptors leads to hyperopia while over activation of D2-like receptors leads to myopia.

Figure 2. Retinal pathway defects alter dopamine signaling and susceptibility to FDM

Several mouse models were tested that had mutations targeting retinal neurons or pathways. Comparing the myopic shift after two weeks of FD with the DOPAC/DA ratio, an indication of DA turnover, showed a strong correlation (R² = 0.92, p<0.001). These results suggest that the level of DA turnover at the start of FD induction may alter the susceptibility to myopia, with lower DA activity predicting greater myopic shifts. (Modified from (Chakraborty and Pardue, 2015)).

Figure 3. Identification of light-triggered D1R activation in specific subpopulations of D1R-containing cells in the retina using the BAC-Drd1a-tdTomato transgenic mice

The BAC-Drd1a-tdTomato transgenic mice (genetic structure shown in A, available from the Jackson Laboratory, Bar Harbor, USA) coupled with c-fos immunohistochemistry allows for the identification of specific retinal subpopulations of D1R-containing cells in response to normal and bright light exposure. Bright light significantly increased c-fos expression in specific subpopulations of D1R-containing cells including horizontal and bipolar cells in retina. B left: the c-fos expression in D1R + retinal neurons in normal light (100–200 lux); B right: the c-fos expression in bright light (2500–5000 lux). White arrows indicate the D1R+ neurons; green arrows indicated c-fos expression; yellow arrows indicated the activated D1R+ neurons (marked by c-fos).