ON pathway mutations increase susceptibility to form-deprivation myopia

Abstract

The ON pathway mutation in nob mice is associated with altered refractive development, and an increased susceptibility to form-deprivation (FD) myopia. In this study, we used mGluR6−/− mice, another ON pathway mutant, to determine whether the nob phenotype was due to the Nyx mutation or abnormal ON pathway transmission. Refractive development under a normal visual environment for mGluR6−/− and age-matched wild-type (WT) mice was measured every 2 weeks from 4 to 16 weeks of age. The response to monocular FD from 4 weeks of age was measured weekly in a separate cohort of mice. Refraction and ocular biometry were obtained using a photorefractor and optical coherence tomography. Retinas were harvested at 16 weeks, and analyzed for dopamine (DA) and DOPAC using high-performance liquid chromatography. Under normal conditions, mGluR6−/− mice were significantly more myopic than their WT controls (refraction at 12 weeks; WT: 9.40 ± 0.16 D, mGluR6−/−: 6.91 ± 0.38 D). Similar to nob mice, two weeks of FD resulted in a significant myopic shift of −5.57 ± 0.72 D in mGluR6−/− mice compared to −1.66 ± 0.19 D in WT animals. No significant axial length changes were observed with either normal or FD visual conditions. At 16 weeks, mGluR6−/− retinas showed significantly lower DOPAC levels (111.2 ± 33.0 pg/mg) compared to their WT counterparts (197.5 ± 11.2 pg/mg). Retinal DA levels were similar between the different genotypes. Our results indicate that reduced retinal DA metabolism/turnover may be associated with increased susceptibility to myopia in mice with ON pathway defect mutations.

Dopamine signaling and myopia development: What are the key challenges

“…With partial form deprivation, retinal DOPAC is decreased locally only in the half of the retina that has been deprived (Ohngemach et al, 1997; Stone et al, 2006) and returns to normal after removal of the diffusers in chickens (Pendrak et al, 1997). Retinal DA levels after form deprivation myopia (FDM) are apparently not altered in wild-type mice (Chakraborty et al, 2015b; Park et al, 2014; Wu et al, 2015), indicating a unique emmetropization process or subtle change of DA in mice. Nonetheless, most studies from multiple species support an association between retinal DA alteration and myopia.…”

Bright Light Suppresses Form-Deprivation Myopia Development With Activation of Dopamine D1 Receptor Signaling in the ON Pathway in Retina

“…Previous studies reported that the ON pathway mutation in mGluR6 À/À and nob mice is associated with myopic shift in refractive development, and leads to an increased susceptibility to FD. 34,35 As recoverinþ OFF-BCs constitute a part of the OFF-BCs, further investigation is needed to determine if changes in the OFF pathway also contribute to myopia development.…”

“…33 Genetic knockout studies indicate that nob mice, which have an ON pathway defect are more susceptible to form deprivation (FD). 34,35 However, there are no reports describing which retinal cell types expressing D1R are activated by BL. Such insight is needed to delineate the signaling pathways mediating D1R control of refraction development.…”

The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease

“…Interestingly, in some myopic patients NYX mutations occur without night blindness (Zhang et al 2007, Zhou et al 2015) suggesting that more subtle alterations of ON-BC signal processing that preserve synaptic transmission may nevertheless cause myopia. The connection of ON-BC dysfunction to myopia is also well supported by the animal models where either pharmacological blockade of ON-BC transmission (Crewther et al 1996, Smith et al 1991) or genetic elimination of NYX or mGluR6 (Chakraborty et al 2015, Pardue et al 2008) similarly exacerbate development of refractive error in experimental models of induced myopia. The molecular basis underlying the involvement of the ON-BC signaling cascade remains unclear, although it is speculated that changes in the levels of neurotransmitter dopamine and/or inputs provided by ON-BC light-driven activity may be among key factors connecting mGluR6 signaling with pathways that control axial growth (Chakraborty & Pardue 2015).…”